Uses and compositions for treatment of psoriatic arthritis

ABSTRACT

The invention provides methods, uses and compositions for the treatment of psoriatic arthritis. The invention describes methods and uses for treating psoriatic arthritis, wherein a TNFα inhibitor, such as a human TNFα antibody, or antigen-binding portion thereof, is used to psoriatic arthritis in a subject. Also described are methods for determining the efficacy of a TNFα inhibitor for treatment of psoriatic arthritis in a subject.

RELATED APPLICATIONS

This application claims the benefit of priority to U.S. provisionalpatent application No. 60/790,909, filed on Apr. 10, 2006; U.S.provisional patent application No. 60/809,770, filed on May 30, 2006;U.S. provisional patent application No. 60/815,489, filed on Jun. 20,2006; U.S. provisional patent application No. 60/858,376, filed on Nov.10, 2006; U.S. provisional patent application No. 60/899,262, filed onFeb. 2, 2007; and U.S. provisional patent application No. 60/909,683,filed on Apr. 2, 2007. The contents of all the above-mentioned priorityapplications are hereby incorporated by reference in their entirety.

BACKGROUND

Tumor necrosis factor has been implicated in the pathophysiology ofpsoriatic arthritis (Partsch et al. (1998) Ann Rheum Dis. 57:691;Ritchlin et al. (1998) J Rheumatol. 25:1544). As referred to herein,psoriatic arthritis (PsA) or psoriasis associated with the skin, refersto chronic inflammatory arthritis which is associated with psoriasis.Psoriasis is a common chronic skin condition that causes red patches onthe body. About 1 in 20 individuals with psoriasis will developarthritis along with the skin condition, and in about 75% of cases,psoriasis precedes the arthritis. PsA exhibits itself in a variety ofways, ranging from mild to severe arthritis, wherein the arthritisusually affects the fingers and the spine. When the spine is affected,the symptoms are similar to those of ankylosing spondylitis. The TNFαinhibitor, or TNFα antibody, or antigen-binding fragment thereof, of theinvention can be used to treat PsA.

SUMMARY OF THE INVENTION

There remains a need for an effective and safe treatment option forpatients suffering from psoriatic arthritis. The instant inventionprovides improved methods and compositions for treating psoriaticarthritis. The invention further provides a means for treating certainsubpopulations of patients who have psoriatic arthritis, includingpatients who have failed therapy or lost responsiveness to treatmentwith TNFα inhibitors. The invention further provides a means by whichthe efficacy of a TNFα inhibitor for the treatment of psoriaticarthritis can be determined. The invention also includes methods fortreating certain types of psoriatic arthritis, e.g., early psoriaticarthritis. Each of the examples described herein describes methods whichcan be used to determine whether a TNFα inhibitor is effective fortreating the given disorder.

In some aspects, the present invention provides a method of determiningthe efficacy of a TNFα inhibitor for treating psoriatic arthritis in asubject comprising determining an ACR20 response of a patient populationhaving psoriatic arthritis and who was administered the TNFα inhibitor,wherein an ACR20 response in at least about 59% of the patientpopulation indicates that the TNFα inhibitor is an effective TNFαinhibitor for the treatment of psoriatic arthritis in a subject. Invarious embodiments, the method further comprises administering theeffective TNFα inhibitor to a subject to treat psoriatic arthritis. Insome embodiments, an ACR20 response in at least about 61% of the patientpopulation indicates that the TNFα inhibitor is an effective TNFαinhibitor for the treatment of psoriatic arthritis in a subject. Inother embodiments, an ACR20 response in at least about 65% of thepatient population indicates that the TNFα inhibitor is an effectiveTNFα inhibitor for the treatment of psoriatic arthritis in a subject. Inyet other embodiments, an ACR20 response in at least about 69% of thepatient population indicates that the TNFα inhibitor is an effectiveTNFα inhibitor for the treatment of psoriatic arthritis in a subject. Insome embodiments, an ACR20 response in at least about 72% of the patientpopulation indicates that the TNFα inhibitor is an effective TNFαinhibitor for the treatment of psoriatic arthritis in a subject. Inother embodiments, an ACR20 response in at least about 75% of thepatient population indicates that the TNFα inhibitor is an effectiveTNFα inhibitor for the treatment of psoriatic arthritis in a subject.

In some aspects, the present invention provides a method of treatingpsoriatic arthritis in a subject comprising administering an effectiveTNFα inhibitor to the subject such that psoriatic arthritis is treated,wherein the effective TNFα inhibitor was previously identified asachieving an ACR20 response in at least about 59% of the patientpopulation. In some aspects, the present invention provides for the useof an effective TNFα inhibitor in the manufacture of a medicament forthe treatment of psoriatic arthritis in a subject, wherein the effectiveTNFα inhibitor was previously identified as achieving an ACR20 responsein at least about 59% of the patient population who was administered theeffective TNFα inhibitor. In some embodiments, the effective TNFαinhibitor was previously identified as achieving an ACR20 response in atleast about 61% of the patient population having psoriatic arthritis. Inother embodiments, the effective TNFα inhibitor was previouslyidentified as achieving an ACR20 response in at least about 65% of thepatient population having psoriatic arthritis. In yet other embodiments,the effective TNFα inhibitor was previously identified as achieving anACR20 response in at least about 69% of the patient population havingpsoriatic arthritis. In some embodiments, the effective TNFα inhibitorwas previously identified as achieving an ACR20 response in at leastabout 72% of the patient population having psoriatic arthritis. In otherembodiments, the effective TNFα inhibitor was previously identified asachieving an ACR20 response in at least about 75% of the patientpopulation having psoriatic arthritis.

In some aspects, the present invention provides a method of determiningthe efficacy of a TNFα inhibitor for treating psoriatic arthritis in asubject comprising: determining a PASI50 response of a patientpopulation having psoriatic arthritis and who was administered the TNFαinhibitor, wherein a PASI50 response in at least about 55% of thepatient population indicates that the TNFα inhibitor is an effectiveTNFα inhibitor for the treatment of psoriatic arthritis in a subject. Insome embodiments, the method further comprises administering theeffective TNFα inhibitor to a subject to treat psoriatic arthritis. Insome embodiments, a PASI50 response in at least about 60% of the patientpopulation indicates that the TNFα inhibitor is an effective TNFαinhibitor for the treatment of psoriatic arthritis in a subject. Inother embodiments, a PASI50 response in at least about 65% of thepatient population indicates that the TNFα inhibitor is an effectiveTNFα inhibitor for the treatment of psoriatic arthritis in a subject. Inyet other embodiments, a PASI50 response in at least about 70% of thepatient population indicates that the TNFα inhibitor is an effectiveTNFα inhibitor for the treatment of psoriatic arthritis in a subject. Insome embodiments, a PASI50 response in at least about 75% of the patientpopulation indicates that the TNFα inhibitor is an effective TNFαinhibitor for the treatment of psoriatic arthritis in a subject. Inother embodiments, a PASI50 response in at least about 80% of thepatient population indicates that the TNFα inhibitor is an effectiveTNFα inhibitor for the treatment of psoriatic arthritis in a subject.

In some aspects, the invention provides a method of treating psoriaticarthritis in a subject comprising administering an effective TNFαinhibitor to the subject such that psoriatic arthritis is treated,wherein the effective TNFα inhibitor was previously identified asachieving a PASI50 response in at least about 55% of the patientpopulation. In other aspects, the invention provides for the use of aneffective TNFα inhibitor in the manufacture of a medicament for thetreatment of psoriatic arthritis in a subject, wherein the effectiveTNFα inhibitor was previously identified as achieving a PASI50 responsein at least about 55% of the patient population who was administered theeffective TNFα inhibitor. In some embodiments, the effective TNFαinhibitor was previously identified as achieving a PASI50 response in atleast about 60% of the patient population having psoriatic arthritis. Inother embodiments, the effective TNFα inhibitor was previouslyidentified as achieving a PASI50 response in at least about 65% of thepatient population having psoriatic arthritis. In yet other embodiments,the effective TNFα inhibitor was previously identified as achieving aPASI50 response in at least about 70% of the patient population havingpsoriatic arthritis. In some embodiments, the effective TNFα inhibitorwas previously identified as achieving a PASI50 response in at leastabout 75% of the patient population having psoriatic arthritis. In yetother embodiments, the effective TNFα inhibitor was previouslyidentified as achieving a PASI50 response in at least about 80% of thepatient population having psoriatic arthritis.

In some aspects, the present invention provides a method of determiningthe efficacy of a TNFα inhibitor for treating psoriatic arthritis in asubject comprising: determining a PASI90 response of a patientpopulation having psoriatic arthritis and who was administered the TNFαinhibitor, wherein a PASI90 response in at least about 43% of thepatient population indicates that the TNFα inhibitor is an effectiveTNFα inhibitor for the treatment of psoriatic arthritis in a subject. Insome embodiments, the method further comprises administering theeffective TNFα inhibitor to a subject to treat psoriatic arthritis. Insome embodiments, a PASI90 response in at least about 50% of the patientpopulation indicates that the TNFα inhibitor is an effective TNFαinhibitor for the treatment of psoriatic arthritis in a subject. In someembodiments, a PASI90 response in at least about 55% of the patientpopulation indicates that the TNFα inhibitor is an effective TNFαinhibitor for the treatment of psoriatic arthritis in a subject. Inother embodiments, a PASI90 response in at least about 60% of thepatient population indicates that the TNFα inhibitor is an effectiveTNFα inhibitor for the treatment of psoriatic arthritis in a subject. Inyet other embodiments, a PASI90 response in at least about 65% of thepatient population indicates that the TNFα inhibitor is an effectiveTNFα inhibitor for the treatment of psoriatic arthritis in a subject. Insome embodiments, a PASI90 response in at least about 70% of the patientpopulation indicates that the TNFα inhibitor is an effective TNFαinhibitor for the treatment of psoriatic arthritis in a subject. Instill yet other embodiments, a PASI90 response in at least about 75% ofthe patient population indicates that the TNFα inhibitor is an effectiveTNFα inhibitor for the treatment of psoriatic arthritis in a subject.

In some aspects, the present invention provides a method of treatingpsoriatic arthritis in a subject comprising administering an effectiveTNFα inhibitor to the subject such that psoriatic arthritis is treated,wherein the effective TNFα inhibitor was previously identified asachieving a PASI90 response in at least about 43% of the patientpopulation. In some aspects, the present invention provides for the useof an effective TNFα inhibitor in the manufacture of a medicament forthe treatment of psoriatic arthritis in a subject, wherein the effectiveTNFα inhibitor was previously identified as achieving a PASI90 responsein at least about 43% of the patient population who was administered theeffective TNFα inhibitor. In some embodiments, the effective TNFαinhibitor was previously identified as achieving a PASI90 response in atleast about 50% of the patient population. In other embodiments, theeffective TNFα inhibitor was previously identified as achieving a PASI90response in at least about 55% of the patient population. In otherembodiments, the effective TNFα inhibitor was previously identified asachieving a PASI90 response in at least about 60% of the patientpopulation. In still yet other embodiments, the effective TNFα inhibitorwas previously identified as achieving a PASI90 response in at leastabout 65% of the patient population. In some embodiments, the effectiveTNFα inhibitor was previously identified as achieving a PASI90 responsein at least about 70% of the patient population. In some embodiments,the effective TNFα inhibitor was previously identified as achieving aPASI90 response in at least about 75% of the patient population.

In some aspects, the present invention provides a method of determiningthe efficacy of a TNFα inhibitor for treating psoriatic arthritis in asubject comprising: determining a PASI100 response of a patientpopulation having psoriatic arthritis and who was administered the TNFαinhibitor, wherein a PASI100 response in at least about 10% of thepatient population indicates that the TNFα inhibitor is an effectiveTNFα inhibitor for the treatment of psoriatic arthritis in a subject. Insome embodiments, the method of the present invention further comprisesadministering the effective TNFα inhibitor to a subject to treatpsoriatic arthritis. In some embodiments, a PASI100 response in at leastabout 20% of the patient population indicates that the TNFα inhibitor isan effective TNFα inhibitor for the treatment of psoriatic arthritis ina subject. In some embodiments, a PASI100 response in at least about 30%of the patient population indicates that the TNFα inhibitor is aneffective TNFα inhibitor for the treatment of psoriatic arthritis in asubject. In other embodiments, a PASI100 response in at least about 40%of the patient population indicates that the TNFα inhibitor is aneffective TNFα inhibitor for the treatment of psoriatic arthritis in asubject. In yet other embodiments, a PASI100 response in at least about45% of the patient population indicates that the TNFα inhibitor is aneffective TNFα inhibitor for the treatment of psoriatic arthritis in asubject.

In some aspects, the present invention provides a method of treatingpsoriatic arthritis in a subject comprising administering an effectiveTNFα inhibitor to the subject such that psoriatic arthritis is treated,wherein the effective TNFα inhibitor was previously identified asachieving a PASI100 response in at least about 10% of the patientpopulation. In yet other aspects, the present invention provides for theuse of an effective TNFα inhibitor in the manufacture of a medicamentfor the treatment of psoriatic arthritis, wherein the effective TNFαinhibitor was previously identified as achieving a PASI100 response inat least about 10% of the patient population who was administered theeffective TNFα inhibitor. In some embodiments, the effective TNFαinhibitor was previously identified as achieving a PASI90 response in atleast about 20% of the patient population. In other embodiments, theeffective TNFα inhibitor was previously identified as achieving a PASI90response in at least about 30% of the patient population. In yet otherembodiments, the effective TNFα inhibitor was previously identified asachieving a PASI90 response in at least about 40% of the patientpopulation. In still yet other embodiments, the effective TNFα inhibitorwas previously identified as achieving a PASI90 response in at leastabout 45% of the patient population.

In some aspects, the present invention provides for the use of a TNFαinhibitor for the manufacture of a medicament for the treatment of mildto moderate psoriatic arthritis (PsA), wherein the medicament is foradministration to a subject who has a PASI score <10. In other aspects,the present invention provides for the use of a TNFα inhibitor for themanufacture of a medicament for the treatment of mild to moderatepsoriatic arthritis (PsA), wherein the medicament is for administrationto a subject who has a PASI score ≧10. In still yet other embodiments,the present invention provides for the use of a TNFα inhibitor in themanufacture of a medicament for the treatment of psoriatic arthritis(PsA) and oligoarthritis.

In some aspects, the present invention provides for a method ofimproving both arthritis and physical functioning of a human subjecthaving PsA and oligoarthritis comprising administering a TNFα inhibitorto the subject. In some aspects, the present invention provides for amethod of treating PsA in a subject having a subtherapeutic response totreatment with a TNFα inhibitor comprising administering the TNFαinhibitor to the subject on a weekly dosing regimen, such that PsA istreated. In some embodiments, the TNFα inhibitor is a TNFα antibody, orantigen-binding portion thereof, or a TNFα fusion protein. In otherembodiments, the TNFα fusion protein is etanercept.

In some aspects, the present invention provides a method of determiningthe efficacy of a human TNFα antibody, or antigen-binding portionthereof, for treating psoriatic arthritis in a subject comprising:determining an ACR50 response of a patient population having psoriaticarthritis and who was administered the human TNFα antibody, orantigen-binding portion thereof, wherein an ACR50 response in at leastabout 42% of the patient population indicates that the human TNFαantibody, or antigen-binding portion thereof, is an effective human TNFαantibody, or antigen-binding portion thereof, for the treatment ofpsoriatic arthritis in a subject. In some embodiments, the methodfurther comprises administering the effective human TNFα antibody, orantigen-binding portion thereof, to a subject to treat psoriaticarthritis. In some embodiments, an ACR50 response in at least about 49%of the patient population indicates that the human TNFα antibody, orantigen-binding portion thereof, is an effective human TNFα antibody, orantigen-binding portion thereof, for the treatment of psoriaticarthritis in a subject. In other embodiments, an ACR50 response in atleast about 52% of the patient population indicates that the human TNFαantibody, or antigen-binding portion thereof, is an effective human TNFαantibody, or antigen-binding portion thereof, for the treatment ofpsoriatic arthritis in a subject. In some embodiments, an ACR50 responsein at least about 58% of the patient population indicates that the humanTNFα antibody, or antigen-binding portion thereof, is an effective humanTNFα antibody, or antigen-binding portion thereof, for the treatment ofpsoriatic arthritis in a subject. In other embodiments, an ACR50response in at least about 60% of the patient population indicates thatthe human TNFα antibody, or antigen-binding portion thereof, is aneffective human TNFα antibody, or antigen-binding portion thereof, forthe treatment of psoriatic arthritis in a subject.

In some aspects, the present invention provides a method of treatingpsoriatic arthritis in a subject comprising administering an effectivehuman TNFα antibody, or antigen-binding portion thereof, to the subjectsuch that psoriatic arthritis is treated, wherein the effective humanTNFα antibody, or antigen-binding portion thereof, was previouslyidentified as achieving an ACR50 response in at least about 42% of thepatient population. In other aspects, the present invention provides forthe use of an effective human TNFα antibody, or antigen-binding portionthereof, in the manufacture of a medicament for the treatment ofpsoriatic arthritis in a subject, wherein the effective human TNFαantibody, or antigen-binding portion thereof, was previously identifiedas achieving an ACR50 response in at least about 42% of the patientpopulation who was administered the effective human TNFα antibody, orantigen-binding portion thereof. In some embodiments, the effectivehuman TNF α antibody, or antigen-binding portion thereof, orantigen-binding portion thereof, was previously identified as achievingan ACR50 response in at least about 49% of the patient population. Inother embodiments, the effective human TNF α antibody, orantigen-binding portion thereof, was previously identified as achievingan ACR50 response in at least about 52% of the patient population. Inyet other embodiments, the effective human TNF α antibody, orantigen-binding portion thereof, was previously identified as achievingan ACR50 response in at least about 58% of the patient population. Insome embodiments, the effective human TNF α antibody, or antigen-bindingportion thereof, was previously identified as achieving an ACR50response in at least about 60% of the patient population.

In some aspects, the present invention provides a method of determiningthe efficacy of a human TNFα antibody, or antigen-binding portionthereof, for treating psoriatic arthritis in a subject comprising:determining an ACR70 response of a patient population having psoriaticarthritis and who was administered the human TNFα antibody, orantigen-binding portion thereof, wherein an ACR70 response in at leastabout 29% of the patient population indicates that the human TNFαantibody, or antigen-binding portion thereof, is an effective human TNFαantibody, or antigen-binding portion thereof, for the treatment ofpsoriatic arthritis in a subject. In some embodiments, the methodfurther comprises administering the effective human TNFα antibody, orantigen-binding portion thereof, to a subject to treat psoriaticarthritis. In some embodiments, an ACR70 response in at least about 31%of the patient population indicates that the human TNFα antibody, orantigen-binding portion thereof, is an effective human TNFα antibody, orantigen-binding portion thereof, for the treatment of psoriaticarthritis in a subject. In other embodiments, an ACR70 response in atleast about 35% of the patient population indicates that the human TNFαantibody, or antigen-binding portion thereof, is an effective human TNFαantibody, or antigen-binding portion thereof, for the treatment ofpsoriatic arthritis in a subject. In other embodiments, an ACR70response in at least about 37% of the patient population indicates thatthe human TNFα antibody, or antigen-binding portion thereof, is aneffective human TNFα antibody, or antigen-binding portion thereof, forthe treatment of psoriatic arthritis in a subject. In yet otherembodiments, an ACR70 response in at least about 40% of the patientpopulation indicates that the human TNFα antibody, or antigen-bindingportion thereof, is an effective human TNFα antibody, or antigen-bindingportion thereof, for the treatment of psoriatic arthritis in a subject.

In some aspects, the present invention provides a method of treatingpsoriatic arthritis in a subject comprising administering an effectivehuman TNFα antibody, or antigen-binding portion thereof, to the subjectsuch that psoriatic arthritis is treated, wherein the effective humanTNFα antibody, or antigen-binding portion thereof, was previouslyidentified as achieving an ACR70 response in at least about 29% of thepatient population. In other embodiments, the present invention providesfor the use of an effective human TNFα antibody, or antigen-bindingportion thereof, in the manufacture of a medicament for the treatment ofpsoriatic arthritis in a subject, wherein the effective human TNFαantibody, or antigen-binding portion thereof, was previously identifiedas achieving an ACR70 response in at least about 29% of the patientpopulation who was administered the human TNFα antibody, orantigen-binding portion thereof. In some embodiments, the effectivehuman TNF α antibody, or antigen-binding portion thereof, was previouslyidentified as achieving an ACR70 response in at least about 31% of thepatient population. In other embodiments, the effective human TNF αantibody, or antigen-binding portion thereof, was previously identifiedas achieving an ACR70 response in at least about 35% of the patientpopulation. In yet other embodiments, the effective human TNF αantibody, or antigen-binding portion thereof, was previously identifiedas achieving an ACR70 response in at least about 37% of the patientpopulation. In some embodiments, the effective human TNF α antibody, orantigen-binding portion thereof, was previously identified as achievingan ACR70 response in at least about 40% of the patient population.

In some aspects, the present invention provides a method of determiningthe efficacy of a human TNFα antibody, or antigen-binding portionthereof, for treating psoriatic arthritis in a subject comprising:determining a PASI75 response of a patient population having psoriaticarthritis and who was administered the human TNFα antibody, orantigen-binding portion thereof, wherein a PASI75 response in at leastabout 65% of the patient population indicates that the human TNFαantibody, or antigen-binding portion thereof, is an effective human TNFαantibody, or antigen-binding portion thereof, for the treatment ofpsoriatic arthritis in a subject. In some embodiments, the methodfurther comprises administering the effective human TNFα antibody, orantigen-binding portion thereof, to a subject to treat psoriaticarthritis. In other embodiments, a PASI75 response in at least about 70%of the patient population indicates that the human TNFα antibody, orantigen-binding portion thereof, is an effective human TNFα antibody, orantigen-binding portion thereof, for the treatment of psoriaticarthritis in a subject. In some embodiments, a PASI75 response in atleast about 75% of the patient population indicates that the human TNFαantibody, or antigen-binding portion thereof, is an effective human TNFαantibody, or antigen-binding portion thereof, for the treatment ofpsoriatic arthritis in a subject.

In some aspects, the present invention provides a method of treatingpsoriatic arthritis in a subject comprising administering an effectivehuman TNFα antibody, or antigen-binding portion thereof, to the subjectsuch that psoriatic arthritis is treated, wherein the effective humanTNFα antibody, or antigen-binding portion thereof, was previouslyidentified as achieving a PASI75 response in at least about 65% of thepatient population. In some aspects, the present invention provides forthe use of an effective human TNFα antibody, or antigen-binding portionthereof, in the manufacture of a medicament for the treatment ofpsoriatic arthritis in a subject, wherein the effective human TNFαantibody, or antigen-binding portion thereof, was previously identifiedas achieving a PASI75 response in at least about 65% of the patientpopulation who was administered the effective human TNFα antibody, orantigen-binding portion thereof. In some embodiments, the effectivehuman TNF α antibody, or antigen-binding portion thereof, was previouslyidentified as achieving a PASI75 response in at least about 70% of thepatient population. In other embodiments, the effective human TNF αantibody, or antigen-binding portion thereof, was previously identifiedas achieving a PASI75 response in at least about 75% of the patientpopulation.

In some aspects, the present invention provides for a method ofdetermining the efficacy of a human TNFα antibody, or antigen-bindingportion thereof, for treating psoriatic arthritis in a subjectcomprising: determining a PGA response of “Clear” or “Almost Clear,” ofa patient population having psoriatic arthritis and who was administeredthe human TNFα antibody, or antigen-binding portion thereof, wherein aPGA response of “Clear” or “Almost Clear,” in at least about 30% of thepatient population indicates that the human TNFα antibody, orantigen-binding portion thereof, is an effective human TNFα antibody, orantigen-binding portion thereof, for the treatment of psoriaticarthritis in a subject. In some embodiments, the method furthercomprises, administering the effective human TNFα antibody, orantigen-binding portion thereof, to a subject to treat psoriaticarthritis. In yet other embodiments, a PGA response of “Clear” or“Almost Clear,” in at least about 45% of the patient populationindicates that the human TNFα antibody, or antigen-binding portionthereof, is an effective human TNFα antibody, or antigen-binding portionthereof, for the treatment of psoriatic arthritis in a subject. In otherembodiments, a PGA response of “Clear” or “Almost Clear,” in at leastabout 60% of the patient population indicates that the human TNFαantibody, or antigen-binding portion thereof, is an effective human TNFαantibody, or antigen-binding portion thereof, for the treatment ofpsoriatic arthritis in a subject. In still yet other embodiments, a PGAresponse of “Clear” or “Almost Clear,” in at least about 75% of thepatient population indicates that the human TNFα antibody, orantigen-binding portion thereof, is an effective human TNFα antibody, orantigen-binding portion thereof, for the treatment of psoriaticarthritis in a subject. In other embodiments, a PGA response of “Clear”or “Almost Clear,” in at least about 80% of the patient populationindicates that the human TNFα antibody, or antigen-binding portionthereof, is an effective human TNFα antibody, or antigen-binding portionthereof, for the treatment of psoriatic arthritis in a subject.

In some aspects, the present invention provides a method of treatingpsoriatic arthritis in a subject comprising administering an effectivehuman TNFα antibody, or antigen-binding portion thereof, to the subjectsuch that psoriatic arthritis is treated, wherein the effective humanTNFα antibody, or antigen-binding portion thereof, was previouslyidentified as achieving a PGA response of “Clear” or “Almost Clear,” inat least about 30% of the patient population. In other aspects, thepresent invention provides for the use of an effective human TNFαantibody, or antigen-binding portion thereof, in the manufacture of amedicament for the treatment of psoriatic arthritis in a subject,wherein the effective human TNFα antibody, or antigen-binding portionthereof, was previously identified as achieving a PGA response of“Clear” or “Almost Clear,” in at least about 30% of the patientpopulation who was administered the effective human TNFα antibody, orantigen-binding portion thereof. In some embodiments, the effectivehuman TNF α antibody, or antigen-binding portion thereof, was previouslyidentified as achieving a PGA response of “Clear” or “Almost Clear,” inat least about 45% of the patient population. In other embodiments, theeffective human TNF α antibody, or antigen-binding portion thereof, waspreviously identified as achieving a PGA response of “Clear” or “AlmostClear,” in at least about 60% of the patient population. In someembodiments, the effective human TNF α antibody, or antigen-bindingportion thereof, was previously identified as achieving a PGA responseof “Clear” or “Almost Clear,” in at least about 75% of the patientpopulation. In other embodiments, the effective human TNF α antibody, orantigen-binding portion thereof, was previously identified as achievinga PGA response of “Clear” or “Almost Clear,” in at least about 80% ofthe patient population.

In some embodiments, the human TNFα antibody, or antigen-binding portionthereof, is administered to the subject in a biweekly dosing regimen. Inother embodiments, the human TNFα antibody, or antigen-binding portionthereof, is administered to the subject in a dose of 40 mg. In yet otherembodiments, the human TNFα antibody, or antigen-binding portionthereof, is administered to the subject subcutaneously.

In some embodiments, the human TNFα antibody, or an antigen-bindingportion thereof, dissociates from human TNFα with a K_(d) of 1×10⁻⁸ M orless and a K_(off) rate constant of 1×10⁻³ s⁻¹ or less, both determinedby surface plasmon resonance, and neutralizes human TNFα cytotoxicity ina standard in vitro L929 assay with an IC₅₀ of 1×10⁻⁷ M or less. Inother embodiments, the human TNFα antibody, or an antigen-bindingportion thereof, has the following characteristics: a) dissociates fromhuman TNFα with a K_(off) rate constant of 1×10⁻³ s⁻¹ or less, asdetermined by surface plasmon resonance; b) has a light chain CDR3domain comprising the amino acid sequence of SEQ ID NO: 3, or modifiedfrom SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5,7 or 8 or by one to five conservative amino acid substitutions atpositions 1, 3, 4, 6, 7, 8 and/or 9; c) has a heavy chain CDR3 domaincomprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8,9, 10 or 11 or by one to five conservative amino acid substitutions atpositions 2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12. In other embodiments,the human TNFα antibody, or an antigen-binding portion thereof,comprises a light chain variable region (LCVR) having a CDR3 domaincomprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8,and comprises a heavy chain variable region (HCVR) having a CDR3 domaincomprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8,9, 10 or 11. In yet other embodiments, the human TNFα antibody, or anantigen-binding portion thereof, comprises a light chain variable region(LCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a heavychain variable region (HCVR) comprising the amino acid sequence of SEQID NO: 2. In still yet other embodiments, the human TNFα antibody, or anantigen-binding portion thereof, is adalimumab.

The invention provides an article of manufacture comprising a packagingmaterial; a TNFα inhibitor; and a label or package insert containedwithin the packaging material indicating that the standardized mortalityrate for the TNFα inhibitor was calculated at about 0.67.

The invention also provides a method of treating a human subject havingrheumatoid arthritis (RA) comprising administering a TNFα inhibitor tothe subject, wherein the subject has previously failed an anti-TNFαtherapy comprising administration of an alternate TNFα antagonist. Inone embodiment, the alternate TNFα antagonist is a biologic agent. Inone embodiment, the biologic agent comprises etanercept or infliximab.In another embodiment, the alternate TNFα antagonist was discontinuedfor a reason selected from the group consisting of no response, lostefficacy, and intolerance.

The invention includes a method for monitoring the effectiveness of aTNFα inhibitor for the treatment of rheumatoid arthritis (RA) in a humansubject comprising administering the TNFα inhibitor to a preselectedpatient population having RA; and determining the effectiveness of theTNFα inhibitor using a baseline ACR score of the patient population andan ACR score of the patient population following administration of theTNFα inhibitor, wherein an ACR20 achieved in about 58-85% of the patientpopulation indicates that the TNFα inhibitor is effective at treatingRA.

The invention also provides a method for monitoring the effectiveness ofa TNFα inhibitor for the treatment of RA in a human subject comprisingadministering the TNFα inhibitor to a preselected patient populationhaving RA; and determining the effectiveness of the TNFα inhibitor usinga baseline ACR score of the patient population and an ACR score of thepatient population following administration of the TNFα inhibitor,wherein an ACR50 achieved in about 30-62% of the patient populationindicates that the TNFα inhibitor is effective at treating RA.

The invention also provides a method for monitoring the effectiveness ofa TNFα inhibitor for the treatment of RA in a human subject comprisingadministering the TNFα inhibitor to a preselected patient populationhaving RA; and determining the effectiveness of the TNFα inhibitor usinga baseline ACR score of the patient population and an ACR score of thepatient population following administration of the TNFα inhibitor,wherein an ACR70 achieved in about 12-38% of the patient populationindicates that the TNFα inhibitor is effective at treating RA. In oneembodiment, preselected patient population has already been administeredthe TNFα inhibitor.

The invention includes a method for monitoring the effectiveness of aTNFα inhibitor for the treatment of RA in a human subject comprisingadministering the TNFα inhibitor to a preselected patient populationhaving rheumatoid arthritis; determining the effectiveness of the TNFαinhibitor using a baseline Disease Activity Score (DAS) 28 score of thepatient population and a DAS28 score of the patient population followingadministration of the TNFα inhibitor, wherein a mean change in the DAS28score of between about −1.9 and -2.8 of the patient population indicatesthat the TNFα inhibitor is effective at treating RA. In one embodiment,the TNFα inhibitor has already been administered to the pre-selectedpatient population.

The invention includes an article of manufacture comprising a packagingmaterial; a TNFα inhibitor; and a label or package insert containedwithin the packaging material indicating that patients receivingtreatment with the TNFα inhibitor can be safely administered apneumonococcal or influenza virus vaccine.

The invention also includes an article of manufacture comprising apackaging material; pneumonococcal or influenza virus vaccine; and alabel or package insert contained within the packaging materialindicating that patients receiving the pneumonococcal or influenza virusvaccine can be safely administered a TNFα inhibitor.

The invention provides a method for treating RA and immunizing against apneumonococcal or influenza virus antigen in a human subject comprisingadministering a TNFα inhibitor to the subject; and administering apneumonococcal or influenza viral vaccine to the subject.

The invention further provides an article of manufacture comprising apackaging material; a TNFα inhibitor; and a label or package insertcontained within the packaging material indicating that in studies ofthe TNFα inhibitor, observed malignancies included melanoma andgranulose cell tumor of the ovary.

The invention includes a method of achieving an early clinical responsein a Hispanic human subject having RA comprising administering a TNFαinhibitor such that an early clinical response in the Hispanic humansubject is achieved. In one embodiment, the Hispanic human subject isVenezuelan. In one embodiment, the early clinical response is determinedusing an assessment test selected from the group consisting of DAS28,TJC28, SJC28, HAQ, pain on VAS, ESR, and CRP. In another embodiment, theinvention includes the early clinical response occurs at about 2 weeksfollowing administration of the TNFα inhibitor.

The invention provides a method of testing the efficacy of a TNFαinhibitor for the rapid improvement of moderate to severe RA in aHispanic patient population comprising administering the TNFα inhibitorto a preselected Hispanic patient population having moderate to severeRA; determining the efficacy of the TNFα inhibitor using a baselineHealth Assessment Questionnaire (HAQ) score of the patient populationand an HAQ score of the patient population following administration ofthe TNFα inhibitor, wherein a decrease in the mean HAQ score of at leastabout −0.5 indicates that the TNFα inhibitor is efficacious for therapid improvement of moderate to severe RA in a Hispanic patientpopulation. In one embodiment, the rapid improvement occurs at about 2weeks following administration of the TNFα inhibitor. In one embodiment,the TNFα inhibitor has already been administered to the pre-selectedpatient population.

The invention provides an article of manufacture comprising a packagingmaterial; a TNFα inhibitor; and a label or package insert containedwithin the packaging material indicating that in studies of the TNFαinhibitor for the treatment of juvenile rheumatoid arthritis (JRA) themost common adverse events (AEs) were infections. In one embodiment, theinfections include mild upper respiratory infections.

In one embodiment, the TNFα inhibitor is administered weekly. In anotherembodiment, the TNFα inhibitor is administered every other week.

The invention provides a method of monitoring the effectiveness of aTNFα inhibitor for the treatment of Crohn's disease comprisingadministering the TNFα inhibitor to a preselected patient populationhaving Crohn's disease; and determining the effectiveness of the TNFαinhibitor using a mean baseline Crohn's Disease Activity Index (CDAI)score of the patient population and a mean CDAI score followingadministration of the TNFα inhibitor, wherein a Δ100 CDAI in at leastabout 60% of the patient population indicates that the TNFα inhibitor iseffective for the treatment of Crohn's disease.

The invention also includes a method of monitoring the effectiveness ofa TNFα inhibitor for the treatment of Crohn's disease comprisingadministering the TNFα inhibitor to a preselected patient populationhaving Crohn's disease; and determining the effectiveness of the TNFαinhibitor by using a mean baseline Crohn's Disease Activity Index (CDAI)score of the patient population and a mean CDAI score followingadministration of the TNFα inhibitor, wherein a CDAI<150 achieved in atleast about 40% of the patient population indicates that the TNFαinhibitor is effective for the treatment of Crohn's disease. In oneembodiment, the patient population comprises patients on concomitantimmunosuppressant (IMM) treatment. In another embodiment, the patientpopulation comprises patients not on concomitant IMM treatment. In oneembodiment, the TNFα inhibitor has already been administered to thepre-selected patient population.

The invention provides a method of testing the efficacy of a TNFαinhibitor to induce and maintain remission of Crohn's disease comprisingadministering the TNFα inhibitor to a preselected patient populationhaving Crohn's disease; and determining the efficacy of the TNFαinhibitor by using a mean baseline Inflammatory Bowel DiseaseQuestionnaire (IBDQ) score of the patient population and a mean IBDQscore following administration of the TNFα inhibitor, wherein anIBDQ >170 achieved in at least about 74% of the patient populationindicates that the TNFα inhibitor is efficacious for inducing andmaintaining remission of Crohn's disease. In one embodiment, the TNFαinhibitor is administered weekly. In another embodiment, the TNFαinhibitor is administered every other week. In one embodiment, the TNFαinhibitor has already been administered to the pre-selected patientpopulation.

The invention further provides a package comprising a TNFα inhibitor anda label, in a position which is visible to prospective purchasers,comprising a printed statement which informs prospective purchasers thatthe median apparent clearance (CL/F) of the TNFα inhibitor ranges fromabout 13.2 to about 15.0 mL/hr. In one embodiment of the invention, thepackage further informs prospective purchasers that concomitant therapywith either immunosuppressant 6 mercaptopurine or azathioprine hasslightly lower or no impact on TNFα inhibitor CL/F. In one embodiment,the anti-TNFα antibody, or antigen-binding portion thereof, is a 40 mgdose.

The invention also includes a method of achieving a PASI50 response andimproving a Physician's Global Assessment (PGA) score to a score of atleast “almost clear” in about 74% of a preselected patient populationhaving psoriatic arthritis (PsA) and a baseline PASI <10, comprisingadministering a TNFα inhibitor to the patient population such that thePASI50 response and the PGA score of “almost clear” is achieved in about74% of the patient population.

The invention includes a method of achieving a PASI75 response andimproving a Physician's Global Assessment (PGA) score to a score of atleast “almost clear” in about 62% of a preselected patient populationhaving PsA and a baseline PASI <10, comprising administering a TNFαinhibitor to the patient population such that the PASI75 response andthe PGA score of “almost clear” is achieved in about 74% of the patientpopulation.

The invention also describes a method of achieving a PASI90 response andimproving a Physician's Global Assessment (PGA) score to a score of atleast “almost clear” in about 38% of a preselected patient populationhaving PsA and a baseline PASI >10, comprising administering a TNFαinhibitor to the patient population such that the PASI90 response isachieved and the PGA score of “almost clear” in about 38% of the patientpopulation is achieved.

In one embodiment of the invention, the PASI response and improved PGAscore is achieved in about 24 weeks.

The invention further describes a method of testing the efficacy of aTNFα inhibitor for the treatment of mild to moderate PsA comprisingtreating a preselected patient population having a PASI score <10 withthe TNFα inhibitor; and determining the efficacy of the TNFα inhibitorusing a baseline Physician Global Assessment (PGA) score of the patientpopulation following administration of the TNFα inhibitor, wherein a PGAscore of “clear” or “almost clear” in at least about 75% of the patientpopulation indicates that the TNFα inhibitor is efficacious for thetreatment of mild to moderate PsA.

The invention describes a method of testing the efficacy of a TNFαinhibitor for the treatment of moderate to severe PsA comprising:treating a preselected patient population having a PASI score >10 withthe TNFα inhibitor; and determining the efficacy of the TNFα inhibitorusing a PGA score of the patient population following administration ofthe TNFα inhibitor, wherein a PGA of “clear” or “almost clear” in 38% ofthe patient population indicates that TNFα inhibitor is efficacious forthe treatment of moderate to severe PsA. In one embodiment, the TNFαinhibitor has already been administered to the pre-selected patientpopulation.

The invention includes a method of testing the efficacy of a TNFαinhibitor for treating mild to moderate PsA comprising: treating apreselected patient population having mild to moderate PsA with the TNFαinhibitor; and determining the efficacy of the TNFα inhibitor using abaseline PASI score of the patient population and a PASI score of thepatient population following administration of the TNFα inhibitor,wherein a PASI50 score in about 77% of the patient population indicatesthat the TNFα inhibitor is efficacious for the treatment of mild tomoderate PsA. In one embodiment, the TNFα inhibitor has already beenadministered to the pre-selected patient population.

The invention provides a method of testing the efficacy of a TNFαinhibitor for treating mild to moderate PsA comprising treating apreselected patient population having mild to moderate PsA with the TNFαinhibitor; and determining the efficacy of the TNFα inhibitor using abaseline PASI score of the patient population and a PASI score of thepatient population following administration of the TNFα inhibitor,wherein a PASI75 score in about 60% of the patient population indicatesthat the TNFα inhibitor is efficacious for the treatment of mild tomoderate PsA. In one embodiment, the TNFα inhibitor has already beenadministered to the pre-selected patient population.

The invention also includes a method of testing the efficacy of a TNFαinhibitor for treating mild to moderate PsA comprising treating apreselected patient population having mild to moderate PsA with the TNFαinhibitor; and determining the efficacy of the TNFα inhibitor using abaseline PASI score of a the patient population and a PASI score of thepatient population following administration of the TNFα inhibitor,wherein a PASI90 score in about 40% of the patient population indicatesthat the TNFα inhibitor is efficacious for the treatment of mild tomoderate PsA.

The invention also includes a method of testing the efficacy of a TNFαinhibitor for treating moderate to severe PsA comprising treating apreselected patient population with the TNFα inhibitor; and determiningthe efficacy of the TNFα inhibitor using a baseline PASI score ofpatient population and a PASI score of the patient population followingadministration of the TNFα inhibitor, wherein a PASI50 score in about74% of the patient population indicates that the TNFα inhibitor isefficacious for the treatment of moderate to severe PsA.

The invention provides a method of testing the efficacy of a TNFαinhibitor for treating moderate to severe PsA comprising treating apreselected patient population having moderate to severe PsA with theTNFα inhibitor; and determining the efficacy of the TNFα inhibitor usinga baseline PASI score of the patient population and a PASI score of thepatient population following administration of the TNFα inhibitor,wherein a PASI75 score in about 59% of the patient population indicatesthat the TNFα inhibitor is efficacious for the treatment of moderate tosevere PsA.

The invention also describes a method of testing the efficacy of a TNFαinhibitor for treating moderate to severe PsA comprising treating apreselected patient population having moderate to severe PsA with theTNFα inhibitor; and determining the efficacy of the TNFα inhibitor usinga baseline PASI score of the patient population and a PASI score of thepatient population following administration of the TNFα inhibitor,wherein a PASI90 score in about 44% of the patient population indicatesthat the TNFα inhibitor is efficacious for the treatment of moderate tosevere PsA. In one embodiment, the TNFα inhibitor has already beenadministered to the pre-selected patient population.

The invention further provides a method for predicting the efficacy of aTNFα inhibitor for improving the PGA score of a subject having mild tomoderate PsA comprising treating the subject with the TNFα inhibitor;determining the post-treatment PASI score of the subject; anddetermining the change between a predetermined baseline PASI score andthe post-treatment PASI score of (b), wherein a PASI50 or a PASI75response indicates that the TNFα inhibitor is efficacious for improvingthe PGA score in the subject having mild to moderate PsA. In oneembodiment, the subject as a baseline PASI <10.

The invention includes a method for predicting the efficacy of a TNFαinhibitor for improving the PGA score of a subject having moderate tosevere PsA comprising treating the subject with the TNFα inhibitor;determining the post-treatment PASI score of the subject; anddetermining the change between a predetermined baseline PASI score andthe post-treatment PASI score of (b), wherein a PASI90 responseindicates that the TNFα inhibitor is efficacious or improving the PGAscore in the subject having moderate to severe PsA. In one embodiment,the subject as a baseline PASI >10.

The invention further provides a method for reducing both jointinflammation and skin disease in a subject having PsA comprisingadministering a TNFα inhibitor such that a PASI50 and an ACR20 responseis achieved.

In one embodiment, a PASI75 response is achieved. In another embodiment,a PASI90 response is achieved. In another embodiment of the invention,an ACR50 response is achieved. In another embodiment of the invention,an ACR70 response is achieved.

The invention also describes a method for determining the efficacy of aTNFα inhibitor for the treatment of PsA comprising administering a TNFαinhibitor to a preselected patient population having psoriasis affectingabout 3% body surface area (BSA) at baseline; and determining theefficacy of the TNFα inhibitor using a baseline ACR score and a baselinePASI score of the patient population and an ACR score and a PASI scoreof the patient population following administration of the TNFαinhibitor, wherein an ACR20 response achieved in about 54% and a PASI50response achieved in about 70% of the patient population indicates thatTNFα inhibitor is efficacious for the treatment of PsA.

The invention also provides a method for determining the efficacy of aTNFα inhibitor for the treatment of PsA comprising administering a TNFαinhibitor to a preselected patient population having psoriasis affectingabout 3% body surface area (BSA) at baseline; and determining theefficacy of the TNFα inhibitor using a baseline ACR score and a baselinePASI score of the patient population and an ACR score and a PASI scoreof the patient population following administration of the TNFαinhibitor, wherein an ACR70 and a PASI75 response achieved in about 26%of the patient population indicates that TNFα inhibitor is efficaciousfor the treatment of PsA.

The invention further provides a method for determining the efficacy ofa TNFα inhibitor for the treatment of PsA comprising administering aTNFα inhibitor to a preselected patient population having psoriasisaffecting about 3% body surface area (BSA) at baseline; and determiningthe efficacy of the TNFα inhibitor using a baseline ACR score and abaseline PASI score of the patient population and an ACR score and aPASI score of the patient population following administration of theTNFα inhibitor, wherein an ACR70 and a PASI90 response achieved in about16% of the patient population indicates that TNFα inhibitor isefficacious for the treatment of PsA. In one embodiment, the TNFαinhibitor has already been administered to the pre-selected patientpopulation.

The invention includes a method of improving both arthritis and physicalfunctioning of a human subject having PsA and oligoarthritis comprisingadministering a TNFα inhibitor to the subject. In one embodiment, theinvention further comprises determining a Health AssessmentQuestionnaire (HAQ) score of the subject following administration of theTNFα inhibitor, wherein the HAQ score decreases by about 0.2 from apre-determined baseline HAQ score of the subject. In one embodiment, theHAQ score decreases by about 0.3. In another embodiment, the HAQ scoredecreases by about 0.5. In one embodiment, the subject has a baselinetender joint count (TJC) <5 or a baseline swollen joint count (SJC) <5.

The invention further provides a method for monitoring the effectivenessof a TNFα inhibitor for the treatment of oligoarthritis associated withPsA comprising administering a TNFα inhibitor to a patient populationhaving PsA and oligoarthritis; and determining the effectiveness of theTNFα inhibitor using a baseline HAQ score of the patient population andan HAQ score of the patient population following administration of theTNFα inhibitor, wherein an average decrease in the HAQ score of about0.2 in the patient population indicates that TNFα inhibitor is effectivefor the treatment of oligoarthritis in human subjects with PsA. In oneembodiment, the subjects in the patient population have a baseline TJC<5 and/or a baseline SJC <5. In another embodiment, the inventionfurther comprises determining the effectiveness of the TNFα inhibitorusing a baseline ACR score of the patient population and an ACR score ofthe patient population following administration of the TNFα inhibitor,wherein an ACR20 response in about 50% of the patient populationindicates that TNFα inhibitor is effective for the treatment ofoligoarthritis in human subjects with PsA. In one embodiment, the TNFαinhibitor has already been administered to the pre-selected patientpopulation when the effectiveness is determined.

The invention also includes a method of determining the effectiveness ofa TNFα inhibitor for treating PsA regardless of the disease duration ina patient comprising administering the TNFα inhibitor to each of twopreselected patient populations, wherein the patient populationscomprise an early patient population having a baseline PsA diseaseduration <about 2 years and a late patient population having a baselinePsA disease duration >about 10 years; determining the effectiveness ofthe TNFα inhibitor by obtaining both an early and a late patientpopulation result using a baseline score from a selected assessment testfrom both the early and late patient populations, wherein the assessmenttest is selected from the group consisting of an HAQ score, a DAS28score, and an ACR score, and a corresponding score from the selectedassessment test in the early and late patient populations followingadministration of the TNFα inhibitor, wherein at least one early patientresult selected from the group consisting of

-   -   i) a mean decrease of about 0.3 in the HAQ score between the two        early patient populations;    -   ii) a mean decrease of about 1.5 in the DAS28 score between the        two early patient populations;    -   iii) an ACR20 response in about 46% of the early patient        population;    -   iv) an ACR50 response in about 38% of the early patient        population; and    -   v) an ACR70 response in about 23% of the early patient        population; and at least one late patient result selected from        the group consisting of    -   i) a mean decrease of about 0.4 in the HAQ score between the two        late patient populations;    -   ii) a mean decrease of about 1.8 in the DAS28 score between the        two late patient populations;    -   iii) an ACR20 response of about 59% of the late patient        population,    -   iv) an ACR50 response of about 36% of the late patient        population, and    -   v) an ACR70 response of about 20% in the late patient        population, indicates that the TNFα inhibitor is effective for        treating PsA regardless of the disease duration in a patient.

The invention also includes a method of for determining the efficacy ofa TNFα inhibitor for achieving complete resolution of general loss ofphysical functional associated with moderate to severe PsA comprisingadministering the TNFα inhibitor to a preselected patient populationhaving moderate to severe psoriatic arthritis; and determining theefficacy of the TNFα inhibitor using a baseline Disability Index of theHAQ (HAQ DI) score of the patient population and an HAQ DI score of thepatient population following administration of the TNFα inhibitor,wherein an HAQ DI score of 0 in about 30-40% of the patient populationindicates that TNFα inhibitor is efficacious for the complete resolutionof general loss of physical functional associated with moderate tosevere PsA. In one embodiment, the TNFα inhibitor has already beenadministered to the pre-selected patient population when the efficacy isdetermined.

The invention provides a method of for determining the efficacy of aTNFα inhibitor for achieving complete resolution of dermatologic-relatedloss of physical functional associated with moderate to severe psoriaticarthritis comprising administering the TNFα inhibitor to a preselectedpatient population having moderate to severe psoriatic arthritis and aBSA >3%; and determining the efficacy of the TNFα inhibitor using abaseline DLQI score from the patient population and a DLQI score of thepatient population following administration of the TNFα inhibitor,wherein a DLQI score of 0 in about 30-40% of the patient populationindicates that TNFα inhibitor is efficacious for the complete resolutionof dermatologic-related loss of physical functional associated withmoderate to severe PsA.

The invention also provides a method for completely resolvingdermatologic-related loss of physical functional in a human subjecthaving moderate to severe PsA comprising administering adalimumab on abiweekly dosing regimen to the subject. In one embodiment, thedermatologic-related loss of physical functional is completely resolvedwithin 12 weeks.

The invention further provides a method of treating a subtherapeuticresponse in a human subject having PsA comprising administering a TNFαinhibitor weekly to the subject. In one embodiment, the human subjecthas a baseline diagnosis of >3 swollen joint count and >3 tender jointcount. In another embodiment, the subtherapeutic response comprises animprovement of less than 20% in both swollen and tender joint countsbetween baseline (week 0) and at a determined time period followingbaseline. In still another embodiment, the determined time periodfollowing baseline is about 12 weeks.

The invention describes a method of achieving an ACR20 response in about41% of a preselected patient population having a subtherapeutic responseto treatment for PsA, comprising administering a TNFα inhibitor weeklyto the patient population until an ACR20 response is achieved in about41% of the patient population.

The invention also describes a method of achieving a PASI50 response inabout 60% of a preselected patient population having a subtherapeuticresponse to treatment for PsA, comprising administering a TNFα inhibitorweekly to the patient population until a PASI50 response is achieved inabout 60% of the patient population.

The invention further provides a method of achieving a PGA score of atleast “almost clear” in about 32% of a preselected patient populationhaving a subtherapeutic response to treatment for PsA, comprisingadministering a TNFα inhibitor weekly to the patient population until aPGA score of at least “almost clear” is achieved in about 32% of thepatient population. In one embodiment, the subtherapeutic responsecomprises an improvement of less a 20% improvement in both swollen andtender joint counts between baseline (week 0) and a determined timeperiod following baseline. In another embodiment, the determined timeperiod following baseline is about 12 weeks.

The invention includes a method of treating ankylosing spondylitis (AS)in a subject comprising subcutaneously administering to the subject aTNFα inhibitor on a biweekly dosing regimen, wherein the serum troughconcentration level of the TNFα inhibitor in the subject is no less thanabout 6-7 μg/mL. In one embodiment, the TNFα inhibitor is administeredin combination with methotrexate.

The invention also provides a method of treating AS in a subjectcomprising subcutaneously administering to the subject a TNFα inhibitoron a biweekly dosing regimen in combination with methotrexate, whereinthe serum trough concentration level of TNFα inhibitor in the subject isno less than about 7-9 μg/mL.

The invention describes a package comprising a TNFα inhibitor and alabel, in a position which is visible to prospective purchasers,comprising a printed statement which informs prospective purchasers thatTNFα inhibitor mean steady-state trough concentrations of approximately6-7 μg/mL and 7-9 μg/mL were observed without and with methotrexate,respectively.

The invention describes a method of testing the effectiveness of a TNFαinhibitor for the treatment of AS comprising administering the TNFαinhibitor to a preselected patient population having AS and determiningthe effectiveness of the TNFα inhibitor using the Assessment inAnkylosing Spondylitis (ASAS) response rate in the patient population,wherein an ASAS20 response rate in about 68% of the patient populationindicates the TNFα inhibitor is effective for the treatment of AS.

The invention further includes a method of testing the efficacy of aTNFα inhibitor for the treatment of AS administering the TNFα inhibitorto a preselected patient population having AS; and determining theefficacy of the TNFα inhibitor using the presence of anti-TNFα inhibitorantibodies in the serum of subjects of the patient population incorrelation with a baseline ASAS score from the patient population andan ASAS score of the patient population following administration of theTNFα inhibitor, wherein the TNFα inhibitor is effective for treating ASif an ASAS20 response is achieved in about 76% of patients determined ashaving no anti-TNFα inhibitor antibodies in the serum. In oneembodiment, the TNFα inhibitor has already been administered to thepre-selected patient population when the efficacy is determined.

The invention also includes a method of testing the efficacy of a TNFαinhibitor for the treatment of AS administering the TNFα inhibitor to apreselected patient population having AS; and determining the efficacyof the TNFα inhibitor using the presence of anti-TNFα inhibitorantibodies in the serum of subjects of the patient population incorrelation with a baseline ASAS score from the patient population andan ASAS score of the patient population following administration of theTNFα inhibitor, wherein the TNFα inhibitor is effective for treating ASis an ASAS20 response is achieved in about 68% of patients determined ashaving anti-TNFα inhibitor antibodies in their serum. In one embodiment,the presence of anti-TNFα inhibitor antibodies is determining usingELISA methods. In one embodiment, the TNFα inhibitor has already beenadministered to the pre-selected patient population when the efficacy isdetermined.

The invention describes a method of testing the efficacy of a TNFαinhibitor for the treatment of AS comprising: administering the TNFαinhibitor to a preselected patient population having AS; and determiningthe efficacy of the TNFα inhibitor using a baseline Bath AnkylosingSpondylitis Activity Index (BASDAI) score of the patient population anda BASDAI score of the patient population following administration of theTNFα inhibitor, wherein a BASDAI20 in about 80% of the patientpopulation indicates that the TNFα inhibitor is effective for treatingAS. In one embodiment, the TNFα inhibitor has already been administeredto the pre-selected patient population when the efficacy is determined.

The invention also includes a method of testing the efficacy of a TNFαinhibitor for the treatment of AS comprising: administering the TNFαinhibitor to a preselected patient population having AS; and determiningthe efficacy of the TNFα inhibitor using a baseline BASDAI score of thepatient population and a BASDAI score of the patient populationfollowing administration of the TNFα inhibitor, wherein a BASDAI50 inabout 67% of the patient population indicates the TNFα inhibitor iseffective for treating AS. In one embodiment, the TNFα inhibitor hasalready been administered to the pre-selected patient population whenthe efficacy is determined.

The invention describes a method of testing the efficacy of a TNFαinhibitor for the treatment of AS comprising: administering the TNFαinhibitor to a preselected patient population having AS; and determiningthe efficacy of the TNFα inhibitor using a baseline BASDAI score of thepatient population and a BASDAI score of the patient populationfollowing administration of the TNFα inhibitor, wherein a BASDAI70 inabout 27% of the patient population indicates the TNFα inhibitor iseffective for treating AS. In one embodiment, the TNFα inhibitor hasalready been administered to the pre-selected patient population whenthe efficacy is determined.

The invention also provides a method of testing the efficacy of a TNFαinhibitor for the treatment of AS comprising: administering the TNFαinhibitor to a preselected patient population having AS; and determiningthe efficacy of the TNFα inhibitor using a baseline ASAS score of thepatient population and an ASAS score of the patient population followingadministration of the TNFα inhibitor, wherein an ASAS20 in about 73% ofthe patient population indicates that TNFα inhibitor is effective fortreating AS. In one embodiment, the TNFα inhibitor has already beenadministered to the pre-selected patient population when the efficacy isdetermined.

The invention describes a method of testing the efficacy of a TNFαinhibitor for the treatment of AS comprising: administering the TNFαinhibitor to a preselected patient population having AS; and determiningthe efficacy of the TNFα inhibitor using a baseline ASAS score of thepatient population and an ASAS score of the patient population followingadministration of the TNFα inhibitor, wherein an ASAS40 in about 60% ofthe patient population indicates the TNFα inhibitor is effective fortreating AS. In one embodiment, the TNFα inhibitor has already beenadministered to the pre-selected patient population when the efficacy isdetermined.

The invention includes method of testing the efficacy of a TNFαinhibitor for the treatment of AS comprising administering the TNFαinhibitor to a preselected patient population having AS; and determiningthe efficacy of the TNFα inhibitor using a baseline ASAS score of thepatient population and an ASAS score of the patient population followingadministration of the TNFα inhibitor, wherein a ASAS70 in about 40% ofthe patient population indicates the TNFα inhibitor is effective fortreating AS. In one embodiment, the TNFα inhibitor has already beenadministered to the pre-selected patient population when the efficacy isdetermined.

The invention also includes a method of predicting long-term efficacy ofa TNFα inhibitor for treatment of AS in a human subject comprisingadministering the TNFα inhibitor to the subject; and predicting thelong-term efficacy using a baseline C-reactive protein (CRP)concentration of the subject and the CRP concentration of the subject atabout 2 weeks following administration of the TNFα inhibitor, wherein aCRP concentration decrease to a normal range indicates that the TNFαinhibitor will be effective for the long term treatment of AS. In oneembodiment, the baseline CRP concentration is about 15 mg/L. In oneembodiment, the TNFα inhibitor has already been administered to thepre-selected patient population when the efficacy is determined.

The invention also provides a method for improving the overall wellbeing of a subject having AS comprising administering a TNFα inhibitorto the subject and determining the physical functioning response of thesubject, wherein an improvement in the physical functioning responseindicates an improvement in the overall well being of the subject. Inone embodiment, the physical functioning response is determined using anindex selected from the group consisting of an ASAS response, a BASDAIresponse, or a combination thereof. In another embodiment, the inventionfurther comprises verifying the improvement in the overall well being ofthe subject using a Health Related Quality of Life (HRQL) score. In oneembodiment, the HRQL score is determined using an index selected fromthe group consisting of a SF-36 mental summary component (SF-36 MCS)score, an AS Quality of Life (ASQoL) score, or a combination thereof.

The invention provides a method for improving the physical functioningresponse of a subject having AS comprising administering a TNFαinhibitor to the subject and determining the overall well being of thesubject, wherein an improvement in the overall well being of the subjectindicates an improvement in the overall physical functioning response ofthe subject. In one embodiment, the overall well being of the subject isdetermining using an HRQL score. In one embodiment, the HRQL score isdetermined using an index selected from the group consisting of a SF-36MCS score, an ASQoL score, or a combination thereof. In one embodiment,the change in the ASQoL score is about 2 or the change in the SF-36 MCSscore is >3 from baseline. In one embodiment, the invention furthercomprises verifying the improvement in the physical functioning responseusing an index selected from the group consisting of an ASAS response, aBASDAI response, or a combination thereof.

The invention includes a method for determining the efficacy of a TNFαinhibitor for improving the overall well being and physical functioningin a human subject having AS comprising

-   -   a) administering the TNFα inhibitor to a patient population        having AS; and    -   b) determining the efficacy of the TNFα inhibitor using a        baseline physical functioning response selected from the group        consisting of an ASAS response, a BASDAI response, or a        combination thereof, and a baseline overall well being response        comprising an HRQL score based on an index selected from the        group consisting of a SF-36 MCS score, an ASQoL score, or a        combination thereof, of the patient population and a        corresponding physical functioning response and overall well        being response of the patient population following        administration of the TNFα inhibitor, wherein the TNFα inhibitor        is effective at improving the overall well being and physical        functioning of the patient population if at least one of the        following is achieved:    -   i) the patient population has an ASAS response of at least        ASAS70 and has a mean SF-36 MCS score change from baseline of at        least about 14;    -   ii) the patient population has an ASAS response between at least        ASAS20 to less than ASAS50 and has a mean ASQoL score change        from baseline of at least about −3.1;    -   iii) the patient population has an ASAS response between at        least ASAS50 to less than ASAS70 and a mean ASQoL score change        from baseline of at least about −4.0;    -   iv) the patient population has an ASAS response between at least        ASAS20 to less than ASAS50 and a mean ASQoL score change from        baseline of at least about −3.1;    -   v) the patient population has an ASAS response of at least        ASAS70 and a mean ASQoL score change from baseline of at least        about −7.5;    -   vi) the patient population has a BASDAI response of at least        BASDAI50 to less than BASDAI70 and a mean SF-36 MCS score change        from baseline of at least about 4.3;    -   vii) the patient population has a BASDAI response of at least        BASDAI70 and a mean SF-36 MCS score change from baseline of at        least about 7.6;    -   viii) the patient population has a BASDAI response of at least        BASDAI50 to less than BASDAI70 and a mean SF-36 MCS score change        from baseline of at least about 4.3;    -   ix) the patient population has a BASDAI response of at least        BASDAI50 to less than BASDAI70 and a mean ASQoL score change        from baseline of at least about −4.0; and    -   x) the patient population has a BASDAI response of at least        BASDAI70 and a mean ASQoL score change from baseline of at least        about −6.8.

The invention also provides a method of reducing both spinal andsacroiliac (SI) joint inflammation in a human subject having AScomprising administering a TNFα inhibitor to the subject such the spinaland sacroiliac (SI) joint inflammation is reduced. In one embodiment,the reduction of spinal and SI joint inflammation is determined usingmagnetic resonance imaging (MRI). In another embodiment, there is atleast about a 53% improvement in spine inflammation from a baselinedetermination to a determination at a time period following baseline. Instill another embodiment, there is at least about a 54% improvement inSI joint inflammation from a baseline determination to a determinationat a time period following baseline. In one embodiment, the time periodfollowing baseline is about 12 weeks.

The invention provides a method of predicting the efficacy of a TNFαinhibitor for the treatment of AS comprising administering the TNFαinhibitor to a human subject having AS; predicting the efficacy of theTNFα inhibitor using a baseline C-reactive protein (CRP) level of thehuman subject and a CRP level following administration of the TNFαinhibitor, wherein a reduction in the CRP level to normal levelsindicates that the TNFα inhibitor is effective at treating AS.

The invention includes a method for monitoring the effectiveness of aTNFα inhibitor for the treatment of pain in a human subject having AScomprising: administering the TNFα inhibitor to the subject; anddetermining the effectiveness of the TNFα inhibitor using a baselinescore from a pain assessment test selected from the group consisting ofTotal Back Pain (TBP) VAS, Nocturnal Pain (NP) VAS, and the SF-36 BodilyPain domain and a score from the pain assessment test followingadministration of the TNFα inhibitor, wherein a change selected from thegroup consisting of about −19.5 for the TBP assessment test; about −19.2for the NP assessment test; and about 19.2 for the SF-36 assessment testindicates that the TNFα inhibitor is effective at reducing pain in asubject having AS.

The invention further provides a method for monitoring the effectivenessof a TNFα inhibitor for the treatment of fatigue in a human subjecthaving AS comprising: administering the TNFα inhibitor to the subject;and determining the effectiveness of the TNFα inhibitor using a either abaseline BASDAI fatigue item score or a baseline SF-36 Vitality itemscore and a BASDAI fatigue item score or a baseline SF-36 Vitality itemscore following administration of the TNFα inhibitor, wherein either achange of about −1.1 for the BASDAI fatigue item or about 13.1 for theSF-36 vitality item indicates that the TNFα inhibitor is effective atreducing fatigue in a subject having AS.

The invention also provides a method for monitoring the effectiveness ofa TNFα inhibitor for treatment of enthesitis in a human subject havingAS comprising: administering the TNFα inhibitor to the subject; anddetermining the effectiveness of the TNFα inhibitor using a baselineBASDAI enthesitis item score and a BASDAI enthesitis item scoredetermined after administration of the TNFα inhibitor, wherein a changeof about −1.79 for the BASDAI enthesitis item indicates that the TNFαinhibitor is effective at reducing enthesitis in a subject having AS.

The invention includes a method for determining the efficacy of a TNFαinhibitor for improving the functional limitations of human subjectshaving moderate to severe chronic plaque psoriasis comprisingadministering the TNFα inhibitor to a preselected patient populationhaving moderate to severe chronic plaque psoriasis; and determining theefficacy of the TNFα inhibitor using a baseline Dermatology Life QualityIndex (DLQI) score from the patient population and a DLQI score from atime period following administration of the TNFα inhibitor, wherein aDLQI score of no or small impact in at least about 83% of the patientpopulation indicates that TNFα inhibitor is efficacious for improvingthe functional limitations of human subjects having moderate to severechronic plaque psoriasis. In one embodiment, the TNFα inhibitor hasalready been administered to the pre-selected patient population whenthe efficacy is determined.

In one embodiment, the TNFα inhibitor is administered weekly to thepatient population. In another embodiment, the TNFα inhibitor isadministered biweekly to the patient population. In still anotherembodiment, the TNFα inhibitor is administered in a multiple variabledose regimen. In one embodiment, the multiple variable dose regimencomprises an induction dose which is at least double the treatment dose.In one embodiment, the induction dose comprises about 80 mg. In oneembodiment, the treatment dose comprises about 40 mg.

The invention provides an article of manufacture comprising: a packagingmaterial; a TNFα inhibitor, and a label or package insert containedwithin the packaging material indicating that a history of systemic orbiologic therapy does not adversely affect efficacy of the TNFαinhibitor in patients.

The invention also provides an article of manufacture comprising: apackaging material; a TNFα inhibitor, and a label or package insertcontained within the packaging material indicating that administrationof the TNFα inhibitor is safe in patients with a history of systemic orbiologic therapy. In one embodiment, the patients have moderate tosevere psoriasis.

The invention includes a method of treating a subtherapeutic response ina subject having moderate to severe plaque psoriasis comprisingadministering a TNFα inhibitor to the subject at an increased dosingrate which is about twice as frequent as the original dosing rate. Inone embodiment, the increased dosing rate is weekly. In anotherembodiment, the subtherapeutic response comprises <PASI50 improvementfrom baseline (week 0) and a determined time period following baseline.In one embodiment, the determined time period following baseline isabout 24 weeks.

The invention includes a package comprising a TNFα inhibitor andinstructions for administering the TNFα inhibitor to a human subject forthe treatment of adults with moderate to severe active ankylosingspondylitis who have had an inadequate response to conventional therapy.

The invention also includes a package comprising a TNFα inhibitor,wherein the package contains, on the label and in a position which isvisible to prospective purchasers, a printed statement which informsprospective purchasers that the TNFα inhibitor is indicated for thetreatment of adults with moderate to severe active ankylosingspondylitis who have had an inadequate response to conventional therapy.

The invention further provides a package comprising a TNFα inhibitor,wherein the package contains, on the label and in a position which isvisible to prospective purchasers, a printed statement which informsprospective purchasers that the recommended dose of the TNFα inhibitorfor patients with ankylosing spondylitis is 40 mg TNFα inhibitoradministered every other week as a single dose via subcutaneousinjection.

The invention also includes a package comprising a TNFα inhibitor,wherein the package contains, on the label and in a position which isvisible to prospective purchasers, a printed statement which informsprospective purchasers that available data suggest that the clinicalresponse is usually achieved within 12 weeks of treatment; and continuedtherapy should be carefully reconsidered in a patient not respondingwithin this time period.

The invention provides a package comprising adalimumab, wherein thepackage contains, on the label and in a position which is visible toprospective purchasers, a printed statement which informs prospectivepurchasers that the proportion of patients who discontinued treatmentdue to adverse events during the double-blind, controlled portion ofStudies I-IX was 5.1% for patients taking the adalimumab and 3.2% forcontrol treated patients.

The invention also provides a package comprising a TNFα inhibitor,wherein the package contains, on the label and in a position which isvisible to prospective purchasers, a printed statement which informsprospective purchasers that the TNFα inhibitor has been shown to have anuncommon undesirable effect in clinical studies selected from the groupconsisting of vaginal infection (including fungal), hyperglycaemia,dysphonia, pharyngeal erythema, wheezing, skin reaction, skinexfoliation, spasm, rheumatoid nodule, shoulder pain, and feeling hot.

The invention further provides a package comprising adalimumab, whereinthe package contains, on the label and in a position which is visible toprospective purchasers, a printed statement which informs prospectivepurchasers of at least one of the following notifications: in the ninecontrolled trials, 17% of patients treated with adalimumab developedinjection site reactions (erythema and/or itching, haemorrhage, pain orswelling), compared to 10% of patients receiving placebo or activecontrol; in the nine controlled trials, the rate of infection was 1.52per patient year in the adalimumab treated patients and 1.40 per patientyear in the placebo and active control-treated patients; in the ninecontrolled trials, 29 malignancies were reported in 2370 adalimumabtreated patients with 1779 patient-years of exposure (16.3 per 1000patient years), and 6 malignancies were reported in 1309 control treatedpatients observed with 872 patient-years of exposure (6.9 per 1000patient years); this included 2 lymphomas in the adalimumab treatedpatients (1.1 per 1000 patient years) and 1 lymphoma in the controltreated patients (1.1 per 1000 patient years); and two patients out of3834 treated with adalimumab in all rheumatoid arthritis, psoriaticarthritis and ankylosing spondylitis studies developed clinical signssuggestive of new-onset lupus-like syndrome.

In one embodiment of the invention, the TNFα inhibitor is selected fromthe group consisting of an anti-TNFα antibody, or an antigen-bindingportion thereof, a TNF fusion protein, or a recombinant TNF bindingprotein. In one embodiment, the TNF fusion protein is etanercept. Inanother embodiment of the invention, the anti-TNFα antibody, orantigen-binding portion thereof, is selected from the group consistingof a chimeric antibody, a humanized antibody, and a multivalentantibody.

In one embodiment of the invention, the anti-TNFα antibody, orantigen-binding portion thereof, is a human antibody.

In another embodiment, the anti-TNFα antibody, or antigen-bindingportion thereof, is an isolated human antibody that dissociates fromhuman TNFα with a K_(d) of 1×10⁻⁸ M or less and a K_(off) rate constantof 1×10⁻³ s⁻¹ or less, both determined by surface plasmon resonance, andneutralizes human TNFα cytotoxicity in a standard in vitro L929 assaywith an IC₅₀ of 1×10⁻⁷ M or less.

In one embodiment of the invention, the anti-TNFα antibody is anisolated human antibody, or antigen-binding portion thereof, with thefollowing characteristics:

a) dissociates from human TNFα with a K_(off) rate constant of 1×10⁻³s⁻¹ or less, as determined by surface plasmon resonance;

b) has a light chain CDR3 domain comprising the amino acid sequence ofSEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alaninesubstitution at position 1, 4, 5, 7 or 8 or by one to five conservativeamino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9;

c) has a heavy chain CDR3 domain comprising the amino acid sequence ofSEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alaninesubstitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or by one to fiveconservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9,10, 11 and/or 12.

In one embodiment of the invention, the anti-TNFα antibody is anisolated human antibody, or an antigen binding portion thereof, with alight chain variable region (LCVR) comprising the amino acid sequence ofSEQ ID NO: 1 and a heavy chain variable region (HCVR) comprising theamino acid sequence of SEQ ID NO: 2. In one embodiment, the anti-TNFαantibody, or antigen-binding portion thereof, is adalimumab.

In one embodiment, the anti-TNFα antibody, or antigen-binding portionthereof, is a 40 mg dose.

In another embodiment, the anti-TNFα antibody, or antigen-bindingportion thereof, is administered subcutaneously.

In another embodiment of the invention, the anti-TNFα antibody, orantigen-binding portion thereof, is infliximab or golimumab.

The invention provides methods for determining the efficacy of a TNFαinhibitor for a disorder in which TNFα activity is detrimental,including rheumatoid arthritis (RA), juvenile RA, ankylosing spondylitis(AS), and psoriatic arthritis (PsA). Each of the examples describedherein describes methods which can be used to determine whether a TNFαinhibitor is effective for treating the given disorder.

The invention describes a method of preventing flare ups associated withjuvenile arthritis (JRA) comprising administering adalimumab to apatient having JRA, such that flare ups are prevented. In oneembodiment, the flare up is prevented from occurring for at least about32 weeks. In another embodiment, the flare up is prevented fromoccurring for at least about 48 weeks.

The invention describes a method for predicting the efficacy of a TNFαinhibitor for the treatment of rheumatoid arthritis in a patientcomprising using a mean baseline score selected from the groupconsisting of a global assessment of the patient's disease activity,pain, function, fatigue, and stiffness, wherein an improvement selectedfrom the group consisting of an improvement of at least about 2.4 in thepatient global score, an improvement of at least about 2.8 in the painscore, an improvement of at least about 2.7 in the function score, animprovement of at least about 0.8 in the fatigue score, and animprovement of at least about 1,2 in the stiffness score, at day 1 frombaseline indicates that the TNFα inhibitor will be effective fortreating RA in the patient.

The invention describes a method for predicting the efficacy of a TNFαinhibitor for the treatment of rheumatoid arthritis in a patientcomprising using the combination of C-reactive protein (CRP) levels ofthe patient and the Patient Activity Score (PAS), wherein an improvementin both the CRP level and the PAS score early in the treatment of thepatient with the TNFα inhibitor indicates that the TNFα inhibitor willbe effective at treating RA in the patient. In one embodiment, the PASscore is determined using the Health Assessment Questionnaire (HAQ).

The invention describes a method for determining the efficacy of a TNFαinhibitor for the treatment of ankylosing spondylitis (AS) in a patientcomprising assessing whether the patient considers his/her currentdisease state satisfactory (PASS).

The invention describes a method of achieving partial remission of apatient having AS comprising administering to the patient a TNFαinhibitor.

The invention also describes method of increasing work productivity in apatient having AS comprising administering to the patient a TNFαinhibitor such that physical functioning is improved.

The invention describes a method for identifying a patient havingpsoriatic arthritis (PsA) who is at risk of aggressive joint destructionand who would benefit from treatment with a TNFα inhibitor, comprisingdetermining the CRP level of the patient, wherein a CRP level of atleast about 2.0 indicates a risk of aggressive joint destruction andthat the patient would benefit from treatment with a TNFα inhibitor.

The invention describes a method for predicting the efficacy of a TNFαinhibitor for improving the quality of life of a patient havingrheumatoid arthritis (RA) in a patient comprising comparing the baselineDAS28 score of the patient with a DAS28 score of the patient followingtreatment with the TNFα inhibitor, wherein an improvement in the DAS28indicates that the TNFα inhibitor will be effective for improving thequality of life in the patient. In one embodiment, the patient hassevere RA.

The invention describes a method of treating late-onset RA comprisingadministering adalimumab to a patient having late-onset RA. In oneembodiment, the patient is over 60 years old.

The invention describes a method for determining the efficacy of a TNFαinhibitor for the treatment of rheumatoid arthritis comprising comparinga pre-determined baseline Simplified Disease Activity Score (SDAI) froma pre-selected patient population having RA to an SDAI score of thepatient population following treatment with the TNFα inhibitor, whereina mean SDAI of no greater than 3.3 in at least about 11% of the patientpopulation indicates that the TNFα inhibitor will be effective fortreating RA.

In one embodiment, the TNFα inhibitor is administered weekly to thepatient population. In one embodiment, the TNFα inhibitor isadministered biweekly to the patient population.

In another embodiment, the TNFα inhibitor is administered in a multiplevariable dose regimen. In one embodiment, the TNFα inhibitor isadministered in a biweekly dosing regimen.

In one embodiment, the TNFα inhibitor is administered as a monotherapy.

In another embodiment, the TNFα inhibitor is administered with anadditional therapeutic agent. In one embodiment, the TNFα inhibitor isadministered with methotrexate. In one embodiment, the patient orpatient population is administered methotrexate in combination with theTNFα inhibitor.

In one embodiment, the TNFα inhibitor is selected from the groupconsisting of a TNFα antibody, or an antigen-binding portion thereof, aTNF fusion protein, or a recombinant TNF binding protein.

In one embodiment, the TNF fusion protein is etanercept.

In one embodiment, the TNFα antibody, or antigen-binding portionthereof, is selected from the group consisting of a chimeric antibody, ahumanized antibody, and a multivalent antibody. In one embodiment, theTNFα antibody, or antigen-binding portion thereof, is a human antibody.

In one embodiment, the TNFα antibody, or antigen-binding portionthereof, is an isolated human antibody that dissociates from human TNFαwith a K_(d) of 1×10⁻⁸ M or less and a K_(off) rate constant of 1×10⁻³s⁻¹ or less, both determined by surface plasmon resonance, andneutralizes human TNFα cytotoxicity in a standard in vitro L929 assaywith an IC₅₀ of 1×10⁻⁷ M or less.

In one embodiment, the TNFα antibody is an isolated human antibody, orantigen-binding portion thereof, with the following characteristics:

a) dissociates from human TNFα with a K_(off) rate constant of 1×10⁻³s⁻¹ or less, as determined by surface plasmon resonance;

b) has a light chain CDR3 domain comprising the amino acid sequence ofSEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alaninesubstitution at position 1, 4, 5, 7 or 8 or by one to five conservativeamino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9;

c) has a heavy chain CDR3 domain comprising the amino acid sequence ofSEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alaninesubstitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or by one to fiveconservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9,10, 11 and/or 12.

In one embodiment, the TNFα antibody is an isolated human antibody, oran antigen binding portion thereof, with a light chain variable region(LCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a heavychain variable region (HCVR) comprising the amino acid sequence of SEQID NO: 2

In one embodiment, the human TNFα antibody, or antigen-binding portionthereof, is adalimumab.

In one embodiment, the TNFα antibody, or antigen-binding portionthereof, is a 40 mg dose.

In one embodiment, the TNFα antibody, or antigen-binding portionthereof, is administered subcutaneously.

In one embodiment, the TNFα antibody, or antigen-binding portionthereof, is infliximab or golimumab.

The invention provides a method of preventing reactivation of latenttuberculosis (LTB) in a patient prior to administration of a TNFαinhibitor to the subject comprising prescreening the patient for TB,wherein the patient is administered isoniazid (INH) if the patient isidentified as being high-risk based on the prescreening results. In oneembodiment, the prescreening method is selected from the groupconsisting of a clinical interview, a PPD test, a chest x-ray, or anycombination thereof. In a further embodiment, the patient isadministered isoniazid (INH) if the patient is identified as beinghigh-risk if the prescreening result is a positive PPD test.

The invention also provides a method of promoting the safety a TNFαinhibitor for the treatment of a disorder in which TNFα activity isdetrimental comprising conveying to a recipient or a medical agent thatstudies have indicated that prescreening a recipient prior to initialadministration of the TNFα inhibitor significantly reduces the chance oflatent TB reactivation.

The invention includes a method of achieving a PASI 100 and animprovement in the quality of life in a subject having psoriaticarthritis comprising administering a TNFα inhibitor to the subject suchthat a PAS100 score and DLQI score of 0 or 1 is achieved.

The invention further provides an article of manufacture comprising: apackaging material; an autoinjector pen filled with a TNFα inhibitor;and a label or package insert contained within the packaging materialindicating that the bioequivalence of the TNFα inhibitor is similarregardless of whether the injection site is the thigh or abdomen.

In one embodiment of the invention, the TNFα inhibitor is selected fromthe group consisting of an anti-TNFα antibody, or an antigen-bindingportion thereof, a TNF fusion protein, or a recombinant TNF bindingprotein. In one embodiment, the TNF fusion protein is etanercept. Inanother embodiment of the invention, the anti-TNFα antibody, orantigen-binding portion thereof, is selected from the group consistingof a chimeric antibody, a humanized antibody, and a multivalentantibody.

In one embodiment of the invention, the anti-TNFα antibody, orantigen-binding portion thereof, is a human antibody.

In another embodiment, the anti-TNFα antibody, or antigen-bindingportion thereof, is an isolated human antibody that dissociates fromhuman TNFα with a K_(d) of 1×10⁻⁸ M or less and a K_(off) rate constantof 1×10⁻³ s⁻¹ or less, both determined by surface plasmon resonance, andneutralizes human TNFα cytotoxicity in a standard in vitro L929 assaywith an IC₅₀ of 1×10⁻⁷ M or less.

In one embodiment of the invention, the anti-TNFα antibody is anisolated human antibody, or antigen-binding portion thereof, with thefollowing characteristics:

a) dissociates from human TNFα with a K_(off) rate constant of 1×10⁻³s⁻¹ or less, as determined by surface plasmon resonance;

b) has a light chain CDR3 domain comprising the amino acid sequence ofSEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alaninesubstitution at position 1, 4, 5, 7 or 8 or by one to five conservativeamino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9;

c) has a heavy chain CDR3 domain comprising the amino acid sequence ofSEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alaninesubstitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or by one to fiveconservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9,10, 11 and/or 12.

In one embodiment of the invention, the anti-TNFα antibody is anisolated human antibody, or an antigen binding portion thereof, with alight chain variable region (LCVR) comprising the amino acid sequence ofSEQ ID NO: 1 and a heavy chain variable region (HCVR) comprising theamino acid sequence of SEQ ID NO: 2. In one embodiment, the anti-TNFαantibody, or antigen-binding portion thereof, is adalimumab.

In one embodiment of the invention, the anti-TNFα antibody, orantigen-binding portion thereof, is infliximab or golimumab oradalimumab.

In one embodiment, the anti-TNFα antibody, or antigen-binding portionthereof, is a 40 mg dose.

In another embodiment, the anti-TNFα antibody, or antigen-bindingportion thereof, is administered subcutaneously.

In one embodiment, the anti-TNFα antibody, or antigen-binding portionthereof, is administered on a biweekly dosing regimen.

In one embodiment, the anti-TNFα antibody, or antigen-binding portionthereof, is administered using a multiple variable dose regimen.

The invention provides methods for determining the efficacy of a TNFαinhibitor for a disorder in which TNFα activity is detrimental,including rheumatoid arthritis (RA), ankylosing spondylitis (AS), andpsoriatic arthritis (PsA). Each of the examples described hereindescribes methods which can be used to determine whether a TNFαinhibitor is effective for treating the given disorder.

The invention also describes an article of manufacture comprising apackaging material; a TNFα inhibitor; and a label or package insertcontained within the packaging material indicating that patients withrheumatoid arthritis (RA) who previously failed therapy with etanerceptor infliximab may benefit from treatment of RA with the human TNFαantibody.

The invention includes a method of promoting a human TNFα antibody to arecipient, the method comprising conveying to the recipient thatpatients with rheumatoid arthritis (RA) who previously failed therapywith etanercept or infliximab may benefit from treatment of RA with thehuman TNFα antibody.

In one embodiment, the invention provides compositions and methodsdescribed herein in combination with an additional therapeutic agent.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a graphic comparison of the mean percent improvement inPASI over 24 weeks between placebo and adalimumab treated patients.

FIG. 2 shows mean changes in TJC and SJC over 48 weeks by diseaseduration for patients in the study of example 6. P≦0.001, † p<0.01 vs.placebo (placebo data not shown for disease duration subgroups). Lastobservation carried forward.

FIG. 3 shows the ACR responses up to 36 weeks after dosage escalation.

FIG. 4 shows the mean percentage PASI improvement in patients whosedosages were increased, up to 36 weeks after dosage escalation. Mean %improvement in PASI by last observation was carried forward.

FIG. 5 shows a graphic depiction of the ACR20 over 24 weeks betweenplacebo and adalimumab treated patients.

FIG. 6 shows a graphic depiction of the ACR50 over 24 weeks betweenplacebo and adalimumab treated patients.

FIG. 7 shows a graphic depiction of the ACR70 over 24 weeks betweenplacebo and adalimumab treated patients.

FIG. 8 shows the mean probability plots of week 24 change in mTSS forbaseline CRP subgroups.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

The term “human TNFα” (abbreviated herein as hTNFα, or simply hTNF), asused herein, is intended to refer to a human cytokine that exists as a17 kD secreted form and a 26 kD membrane associated form, thebiologically active form of which is composed of a trimer ofnoncovalently bound 17 kD molecules. The structure of hTNFα is describedfurther in, for example, Pennica, D., et al. (1984) Nature 312:724-729;Davis, J. M., et al. (1987) Biochemistry 26:1322-1326; and Jones, E. Y.,et al. (1989) Nature 338:225-228. The term human TNFα is intended toinclude recombinant human TNFα (rhTNFα), which can be prepared bystandard recombinant expression methods or purchased commercially (R & DSystems, Catalog No. 210-TA, Minneapolis, Minn.). TNFα is also referredto as TNF.

The term “TNFα inhibitor” includes agents which interfere with TNFαactivity. The term also includes each of the anti-TNFα human antibodiesand antibody portions described herein as well as those described inU.S. Pat. Nos. 6,090,382; 6,258,562; 6,509,015, and in U.S. patentapplication Ser. Nos. 09/801,185 and 10/302,356. In one embodiment, theTNFα inhibitor used in the invention is an anti-TNFα antibody, or afragment thereof, including infliximab (Remicade®, Johnson and Johnson;described in U.S. Pat. No. 5,656,272, incorporated by reference herein),CDP571 (a humanized monoclonal anti-TNF-alpha IgG4 antibody), CDP 870 (ahumanized monoclonal anti-TNF-alpha antibody fragment), an anti-TNF dAb(Peptech), CNTO 148 (golimumab; Medarex and Centocor, see WO 02/12502),and adalimumab (HUMIRA® Abbott Laboratories, a human anti-TNF mAb,described in U.S. Pat. No. 6,090,382 as D2E7). Additional TNF antibodieswhich may be used in the invention are described in U.S. Pat. Nos.6,593,458; 6,498,237; 6,451,983; and 6,448,380, each of which isincorporated by reference herein. In another embodiment, the TNFαinhibitor is a TNF fusion protein, e.g., etanercept (Enbrel®, Amgen;described in WO 91/03553 and WO 09/406476, incorporated by referenceherein). In another embodiment, the TNFα inhibitor is a recombinant TNFbinding protein (r-TBP-I) (Serono).

The term “antibody,” as used herein, is intended to refer toimmunoglobulin molecules comprised of four polypeptide chains, two heavy(H) chains and two light (L) chains inter-connected by disulfide bonds.Each heavy chain is comprised of a heavy chain variable region(abbreviated herein as HCVR or VH) and a heavy chain constant region.The heavy chain constant region is comprised of three domains, CH1, CH2and CH3. Each light chain is comprised of a light chain variable region(abbreviated herein as LCVR or VL) and a light chain constant region.The light chain constant region is comprised of one domain, CL. The VHand VL regions can be further subdivided into regions ofhypervariability, termed complementarity determining regions (CDR),interspersed with regions that are more conserved, termed frameworkregions (FR). Each VH and VL is composed of three CDRs and four FRs,arranged from amino-terminus to carboxy-terminus in the following order:FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The antibodies of the inventionare described in further detail in U.S. Pat. Nos. 6,090,382; 6,258,562;and 6,509,015, each of which is incorporated herein by reference in itsentirety.

The term “antigen-binding portion” or “antigen-binding fragment” of anantibody (or simply “antibody portion”), as used herein, refers to oneor more fragments of an antibody that retain the ability to specificallybind to an antigen (e.g., hTNFα). It has been shown that theantigen-binding function of an antibody can be performed by fragments ofa full-length antibody. Binding fragments include Fab, Fab′, F(ab′)₂,Fabc, Fv, single chains, and single-chain antibodies. Examples ofbinding fragments encompassed within the term “antigen-binding portion”of an antibody include (i) a Fab fragment, a monovalent fragmentconsisting of the VL, VH, CL and CH1 domains; (ii) a F(ab′)₂ fragment, abivalent fragment comprising two Fab fragments linked by a disulfidebridge at the hinge region; (iii) a Fd fragment consisting of the VH andCH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of asingle arm of an antibody, (v) a dAb fragment (Ward et al. (1989) Nature341:544-546), which consists of a VH domain; and (vi) an isolatedcomplementarity determining region (CDR). Furthermore, although the twodomains of the Fv fragment, VL and VH, are coded for by separate genes,they can be joined, using recombinant methods, by a synthetic linkerthat enables them to be made as a single protein chain in which the VLand VH regions pair to form monovalent molecules (known as single chainFv (scFv); see e.g., Bird et al. (1988) Science 242:423-426; and Hustonet al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such singlechain antibodies are also intended to be encompassed within the term“antigen-binding portion” of an antibody. Other forms of single chainantibodies, such as diabodies are also encompassed. Diabodies arebivalent, bispecific antibodies in which VH and VL domains are expressedon a single polypeptide chain, but using a linker that is too short toallow for pairing between the two domains on the same chain, therebyforcing the domains to pair with complementary domains of another chainand creating two antigen binding sites (see e.g., Holliger et al. (1993)Proc. Natl. Acad. Sci. USA 90:6444-6448; Poijak et al. (1994) Structure2:1121-1123). The antibody portions of the invention are described infurther detail in U.S. Pat. Nos. 6,090,382, 6,258,562, 6,509,015, eachof which is incorporated herein by reference in its entirety.

Still further, an antibody or antigen-binding portion thereof may bepart of a larger immunoadhesion molecules, formed by covalent ornoncovalent association of the antibody or antibody portion with one ormore other proteins or peptides. Examples of such immunoadhesionmolecules include use of the streptavidin core region to make atetrameric scFv molecule (Kipriyanov, S. M., et al. (1995) HumanAntibodies and Hybridomas 6:93-101) and use of a cysteine residue, amarker peptide and a C-terminal polyhistidine tag to make bivalent andbiotinylated scFv molecules (Kipriyanov, S. M., et al. (1994) Mol.Immunol. 31:1047-1058). Antibody portions, such as Fab and F(ab′)₂fragments, can be prepared from whole antibodies using conventionaltechniques, such as papain or pepsin digestion, respectively, of wholeantibodies. Moreover, antibodies, antibody portions and immunoadhesionmolecules can be obtained using standard recombinant DNA techniques, asdescribed herein.

A “conservative amino acid substitution,” as used herein, is one inwhich one amino acid residue is replaced with another amino acid residuehaving a similar side chain. Families of amino acid residues havingsimilar side chains have been defined in the art, including basic sidechains (e.g., lysine, arginine, histidine), acidic side chains (e.g.,aspartic acid, glutamic acid), uncharged polar side chains (e.g.,glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine),nonpolar side chains (e.g., alanine, valine, leucine, isoleucine,proline, phenylalanine, methionine, tryptophan), beta-branched sidechains (e.g., threonine, valine, isoleucine) and aromatic side chains(e.g., tyrosine, phenylalanine, tryptophan, histidine).

“Chimeric antibodies” refers to antibodies wherein one portion of eachof the amino acid sequences of heavy and light chains is homologous tocorresponding sequences in antibodies derived from a particular speciesor belonging to a particular class, while the remaining segment of thechains is homologous to corresponding sequences from another species. Inone embodiment, the invention features a chimeric antibody orantigen-binding fragment, in which the variable regions of both lightand heavy chains mimics the variable regions of antibodies derived fromone species of mammals, while the constant portions are homologous tothe sequences in antibodies derived from another species. In a preferredembodiment of the invention, chimeric antibodies are made by graftingCDRs from a mouse antibody onto the framework regions of a humanantibody.

“Humanized antibodies” refer to antibodies which comprise at least onechain comprising variable region framework residues substantially from ahuman antibody chain (referred to as the acceptor immunoglobulin orantibody) and at least one complementarity determining region (CDR)substantially from a non-human-antibody (e.g., mouse). In addition tothe grafting of the CDRs, humanized antibodies typically undergo furtheralterations in order to improve affinity and/or immunogenicity.

The term “multivalent antibody” refers to an antibody comprising morethan one antigen recognition site. For example, a “bivalent” antibodyhas two antigen recognition sites, whereas a “tetravalent” antibody hasfour antigen recognition sites. The terms “monospecific”, “bispecific”,“trispecific”, “tetraspecific”, etc. refer to the number of differentantigen recognition site specificities (as opposed to the number ofantigen recognition sites) present in a multivalent antibody. Forexample, a “monospecific” antibody's antigen recognition sites all bindthe same epitope. A “bispecific” or “dual specific” antibody has atleast one antigen recognition site that binds a first epitope and atleast one antigen recognition site that binds a second epitope that isdifferent from the first epitope. A “multivalent monospecific” antibodyhas multiple antigen recognition sites that all bind the same epitope. A“multivalent bispecific” antibody has multiple antigen recognitionsites, some number of which bind a first epitope and some number ofwhich bind a second epitope that is different from the first epitope

The term “human antibody,” as used herein, is intended to includeantibodies having variable and constant regions derived from humangermline immunoglobulin sequences. The human antibodies of the inventionmay include amino acid residues not encoded by human germlineimmunoglobulin sequences (e.g., mutations introduced by random orsite-specific mutagenesis in vitro or by somatic mutation in vivo), forexample in the CDRs and in particular CDR3. However, the term “humanantibody”, as used herein, is not intended to include antibodies inwhich CDR sequences derived from the germline of another mammalianspecies, such as a mouse, have been grafted onto human frameworksequences.

The term “recombinant human antibody”, as used herein, is intended toinclude all human antibodies that are prepared, expressed, created orisolated by recombinant means, such as antibodies expressed using arecombinant expression vector transfected into a host cell (describedfurther below), antibodies isolated from a recombinant, combinatorialhuman antibody library (described further below), antibodies isolatedfrom an animal (e.g., a mouse) that is transgenic for humanimmunoglobulin genes (see e.g., Taylor et al. (1992) Nucl. Acids Res.20:6287) or antibodies prepared, expressed, created or isolated by anyother means that involves splicing of human immunoglobulin genesequences to other DNA sequences. Such recombinant human antibodies havevariable and constant regions derived from human germline immunoglobulinsequences. In certain embodiments, however, such recombinant humanantibodies are subjected to in vitro mutagenesis (or, when an animaltransgenic for human Ig sequences is used, in vivo somatic mutagenesis)and thus the amino acid sequences of the VH and VL regions of therecombinant antibodies are sequences that, while derived from andrelated to human germline VH and VL sequences, may not naturally existwithin the human antibody germline repertoire in vivo.

Such chimeric, humanized, human, and dual specific antibodies can beproduced by recombinant DNA techniques known in the art, for exampleusing methods described in PCT International Application No.PCT/US86/02269; European Patent Application No. 184,187; European PatentApplication No. 171,496; European Patent Application No. 173,494; PCTInternational Publication No. WO 86/01533; U.S. Pat. No. 4,816,567;European Patent Application No. 125,023; Better et al. (1988) Science240:1041-1043; Liu et al. (1987) Proc. Natl. Acad. Sci. USA84:3439-3443; Liu et al. (1987) J. Immunol. 139:3521-3526; Sun et al.(1987) Proc. Natl. Acad. Sci. USA 84:214-218; Nishimura et al. (1987)Cancer Res. 47:999-1005; Wood et al. (1985) Nature 314:446-449; Shaw etal. (1988) J. Natl. Cancer Inst. 80:1553-1559); Morrison (1985) Science229:1202-1207; Oi et al. (1986) BioTechniques 4:214; U.S. Pat. No.5,225,539; Jones et al. (1986) Nature 321:552-525; Verhoeyan et al.(1988) Science 239:1534; and Beidler et al. (1988) J. Immunol.141:4053-4060, Queen et al., Proc. Natl. Acad. Sci. USA 86:10029-10033(1989), U.S. Pat. No. 5,530,101, U.S. Pat. No. 5,585,089, U.S. Pat. No.5,693,761, U.S. Pat. No. 5,693,762, Selick et al., WO 90/07861, andWinter, U.S. Pat. No. 5,225,539.

An “isolated antibody,” as used herein, is intended to refer to anantibody that is substantially free of other antibodies having differentantigenic specificities (e.g., an isolated antibody that specificallybinds hTNFα is substantially free of antibodies that specifically bindantigens other than hTNFα). An isolated antibody that specifically bindshTNFα may, however, have cross-reactivity to other antigens, such asTNFα molecules from other species. Moreover, an isolated antibody may besubstantially free of other cellular material and/or chemicals.

A “neutralizing antibody,” as used herein (or an “antibody thatneutralized hTNFα activity”), is intended to refer to an antibody whosebinding to hTNFα results in inhibition of the biological activity ofhTNFα. This inhibition of the biological activity of hTNFα can beassessed by measuring one or more indicators of hTNFα biologicalactivity, such as hTNFα-induced cytotoxicity (either in vitro or invivo), hTNFα-induced cellular activation and hTNFα binding to hTNFαreceptors. These indicators of hTNFα biological activity can be assessedby one or more of several standard in vitro or in vivo assays known inthe art (see U.S. Pat. No. 6,090,382). Preferably, the ability of anantibody to neutralize hTNFα activity is assessed by inhibition ofhTNFα-induced cytotoxicity of L929 cells. As an additional oralternative parameter of hTNFα activity, the ability of an antibody toinhibit hTNFα-induced expression of ELAM-1 on HUVEC, as a measure ofhTNFα-induced cellular activation, can be assessed.

The term “surface plasmon resonance,” as used herein, refers to anoptical phenomenon that allows for the analysis of real-time biospecificinteractions by detection of alterations in protein concentrationswithin a biosensor matrix, for example using the BIAcore system(Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.). Forfurther descriptions, see Example 1 of U.S. Pat. No. 6,258,562 andJonsson et al. (1993) Ann. Biol. Clin. 51:19; Jönsson et al. (1991)Biotechniques 11:620-627; Johnsson et al. (1995) J. Mol. Recognit.8:125; and Johnnson et al. (1991) Anal. Biochem. 198:268.

The term “K_(off)”, as used herein, is intended to refer to the off rateconstant for dissociation of an antibody from the antibody/antigencomplex.

The term “K_(d)”, as used herein, is intended to refer to thedissociation constant of a particular antibody-antigen interaction.

The term “IC₅₀” as used herein, is intended to refer to theconcentration of the inhibitor required to inhibit the biologicalendpoint of interest, e.g., neutralize cytotoxicity activity.

The term “dose,” as used herein, refers to an amount of TNFα inhibitorwhich is administered to a subject.

The term “dosing”, as used herein, refers to the administration of asubstance (e.g., an anti-TNFα antibody) to achieve a therapeuticobjective (e.g., treatment of psoriatic arthritis).

A “dosing regimen” describes a treatment schedule for a TNFα inhibitor,e.g., a treatment schedule over a prolonged period of time and/orthroughout the course of treatment, e.g. administering a first dose of aTNFα inhibitor at week 0 followed by a second dose of a TNFα inhibitoron a biweekly dosing regimen.

The terms “biweekly dosing regimen”, “biweekly dosing”, and “biweeklyadministration”, as used herein, refer to the time course ofadministering a substance (e.g., an anti-TNFα antibody) to a subject toachieve a therapeutic objective, e.g, throughout the course oftreatment. The biweekly dosing regimen is not intended to include aweekly dosing regimen. Preferably, the substance is administered every9-19 days, more preferably, every 11-17 days, even more preferably,every 13-15 days, and most preferably, every 14 days. In one embodiment,the biweekly dosing regimen is initiated in a subject at week 0 oftreatment. In another embodiment, a maintenance dose is administered ona biweekly dosing regimen. In one embodiment, both the loading andmaintenance doses are administered according to a biweekly dosingregimen. In one embodiment, biweekly dosing includes a dosing regimenwherein doses of a TNFα inhibitor are administered to a subject everyother week beginning at week 0. In one embodiment, biweekly dosingincludes a dosing regimen where doses of a TNFα inhibitor areadministered to a subject every other week consecutively for a giventime period, e.g., 4 weeks, 8 weeks, 16, weeks, 24 weeks, 26 weeks, 32weeks, 36 weeks, 42 weeks, 48 weeks, 52 weeks, 56 weeks, etc. Biweeklydosing methods are also described in US 20030235585, incorporated byreference herein.

The term “combination” as in the phrase “a first agent in combinationwith a second agent” includes co-administration of a first agent and asecond agent, which for example may be dissolved or intermixed in thesame pharmaceutically acceptable carrier, or administration of a firstagent, followed by the second agent, or administration of the secondagent, followed by the first agent. The present invention, therefore,includes methods of combination therapeutic treatment and combinationpharmaceutical compositions.

The term “concomitant” as in the phrase “concomitant therapeutictreatment” includes administering an agent in the presence of a secondagent. A concomitant therapeutic treatment method includes methods inwhich the first, second, third, or additional agents areco-administered. A concomitant therapeutic treatment method alsoincludes methods in which the first or additional agents areadministered in the presence of a second or additional agents, whereinthe second or additional agents, for example, may have been previouslyadministered. A concomitant therapeutic treatment method may be executedstep-wise by different actors. For example, one actor may administer toa subject a first agent and a second actor may to administer to thesubject a second agent, and the administering steps may be executed atthe same time, or nearly the same time, or at distant times, so long asthe first agent (and additional agents) are after administration in thepresence of the second agent (and additional agents). The actor and thesubject may be the same entity (e.g., human).

The term “combination therapy”, as used herein, refers to theadministration of two or more therapeutic substances, e.g., an anti-TNFαantibody and another drug. The other drug(s) may be administeredconcomitant with, prior to, or following the administration of ananti-TNFα antibody.

The term “treatment,” as used within the context of the presentinvention, is meant to include therapeutic treatment, as well asprophylactic or suppressive measures, for the treatment of psoriaticarthritis. For example, in one embodiment, the term “treatment” or“treating” refers to reducing signs and symptoms of active arthritis. Inone embodiment, the term “treatment” or “treating” refers to inhibitingthe progression of structural damage in patients with psoriaticarthritis. In one embodiment, the term “treatment” or “treating” refersto improving physical function in patients with psoriatic arthritis.

The term treatment may, for example, include administration of a TNFαinhibitor prior to or following the onset of psoriatic arthritis therebypreventing or removing signs of the disease or disorder. As anotherexample, administration of a TNFα inhibitor after clinical manifestationof psoriatic arthritis to combat the symptoms and/or complications anddisorders associated with psoriatic arthritis comprises “treatment” ofthe disease. Further, administration of the agent after onset and afterclinical symptoms and/or complications have developed whereadministration affects clinical parameters of the disease or disorderand perhaps amelioration of the disease, comprises “treatment” ofpsoriatic arthritis.

Those “in need of treatment” include mammals, such as humans, alreadyhaving psoriatic arthritis, including those in which the disease ordisorder is to be prevented.

Various aspects of the invention are described in further detail herein.

The invention provides improved uses and compositions for treatingpsoriatic arthritis with a TNFα inhibitor, e.g., a human TNFα antibody,or an antigen-binding portion thereof. Compositions and articles ofmanufacture, including kits, relating to the methods and uses fortreating psoriatic arthritis are also contemplated as part of theinvention.

II. TNF Inhibitors

A TNFα inhibitor which is used in the methods and compositions of theinvention includes any agent which interferes with TNFα activity. In apreferred embodiment, the TNFα inhibitor can neutralize TNFα activity,particularly detrimental TNFα activity which is associated with Crohn'sdisease, and related complications and symptoms.

In one embodiment, the TNFα inhibitor used in the invention is an TNFαantibody (also referred to herein as a TNFα antibody), or anantigen-binding fragment thereof, including chimeric, humanized, andhuman antibodies. Examples of TNFα antibodies which may be used in theinvention include, but not limited to, infliximab (Remicade®, Johnsonand Johnson; described in U.S. Pat. No. 5,656,272, incorporated byreference herein), CDP571 (a humanized monoclonal anti-TNF-alpha IgG4antibody), CDP 870 (a humanized monoclonal anti-TNF-alpha antibodyfragment), an anti-TNF dAb (Peptech), CNTO 148 (golimumab; Medarex andCentocor, see WO 02/12502), and adalimumab (HUMIRA® Abbott Laboratories,a human anti-TNF mAb, described in U.S. Pat. No. 6,090,382 as D2E7).Additional TNF antibodies which may be used in the invention aredescribed in U.S. Pat. Nos. 6,593,458; 6,498,237; 6,451,983; and6,448,380, each of which is incorporated by reference herein.

Other examples of TNFα inhibitors which may be used in the methods andcompositions of the invention include etanercept (Enbrel, described inWO 91/03553 and WO 09/406476), soluble TNF receptor Type I, a pegylatedsoluble TNF receptor Type I (PEGs TNF-R1), p55TNFR1gG (Lenercept), andrecombinant TNF binding protein (r-TBP-I) (Serono).

In one embodiment, the term “TNFα inhibitor” excludes infliximab. In oneembodiment, the term “TNFα inhibitor” excludes adalimumab. In anotherembodiment, the term “TNFα inhibitor” excludes adalimumab andinfliximab.

In one embodiment, the term “TNFα inhibitor” excludes etanercept, and,optionally, adalimumab, infliximab, and adalimumab and infliximab.

In one embodiment, the term “TNFα antibody” excludes infliximab. In oneembodiment, the term “TNFα antibody” excludes adalimumab. In anotherembodiment, the term “TNFα antibody” excludes adalimumab and infliximab.

In one embodiment, the invention features uses and composition fortreating or determining the efficacy of a TNFα inhibitor for thetreatment of Crohn's disease, wherein the TNFα antibody is an isolatedhuman antibody, or antigen-binding portion thereof, that binds to humanTNFα with high affinity and a low off rate, and also has a highneutralizing capacity. Preferably, the human antibodies used in theinvention are recombinant, neutralizing human anti-hTNFα antibodies. Themost preferred recombinant, neutralizing antibody of the invention isreferred to herein as D2E7, also referred to as HUMIRA® or adalimumab(the amino acid sequence of the D2E7 VL region is shown in SEQ ID NO: 1;the amino acid sequence of the D2E7 VH region is shown in SEQ ID NO: 2).The properties of D2E7 (adalimumab/HUMIRA®) have been described inSalfeld et al., U.S. Pat. Nos. 6,090,382, 6,258,562, and 6,509,015,which are each incorporated by reference herein. The methods of theinvention may also be performed using chimeric and humanized murineanti-hTNFα antibodies which have undergone clinical testing fortreatment of rheumatoid arthritis (see e.g., Elliott, M. J., et al.(1994) Lancet 344:1125-1127; Elliot, M. J., et al. (1994) Lancet344:1105-1110; Rankin, E. C., et al. (1995) Br. J. Rheumatol.34:334-342).

In one embodiment, the method of the invention includes determining theefficacy of D2E7 antibodies and antibody portions, D2E7-relatedantibodies and antibody portions, or other human antibodies and antibodyportions with equivalent properties to D2E7, such as high affinitybinding to hTNFα with low dissociation kinetics and high neutralizingcapacity, for the treatment of Crohn's disease. In one embodiment, theinvention provides treatment with an isolated human antibody, or anantigen-binding portion thereof, that dissociates from human TNFα with aK_(d) of 1×10⁻⁸ M or less and a K_(off) rate constant of 1×10⁻³ s⁻¹ orless, both determined by surface plasmon resonance, and neutralizeshuman TNFα cytotoxicity in a standard in vitro L929 assay with an IC₅₀of 1×10⁻⁷ M or less. More preferably, the isolated human antibody, orantigen-binding portion thereof, dissociates from human TNFα with aK_(off) of 5×10⁻⁴ s⁻¹ or less, or even more preferably, with a K_(off)of 1×10⁻⁴ s⁻¹ or less. More preferably, the isolated human antibody, orantigen-binding portion thereof, neutralizes human TNFα cytotoxicity ina standard in vitro L929 assay with an IC₅₀ of 1×10⁻⁸ M or less, evenmore preferably with an IC₅₀ of 1×10⁻⁹ M or less and still morepreferably with an IC₅₀ of 1×10⁻¹⁰ M or less. In a preferred embodiment,the antibody is an isolated human recombinant antibody, or anantigen-binding portion thereof.

It is well known in the art that antibody heavy and light chain CDR3domains play an important role in the binding specificity/affinity of anantibody for an antigen. Accordingly, in another aspect, the inventionpertains to treating Crohn's disease by administering human antibodiesthat have slow dissociation kinetics for association with hTNFα and thathave light and heavy chain CDR3 domains that structurally are identicalto or related to those of D2E7. Position 9 of the D2E7 VL CDR3 can beoccupied by Ala or Thr without substantially affecting the K_(off).Accordingly, a consensus motif for the D2E7 VL CDR3 comprises the aminoacid sequence: Q-R-Y-N-R-A-P-Y-(T/A) (SEQ ID NO: 3). Additionally,position 12 of the D2E7 VH CDR3 can be occupied by Tyr or Asn, withoutsubstantially affecting the IC_(off). Accordingly, a consensus motif forthe D2E7 VH CDR3 comprises the amino acid sequence:V-S-Y-L-S-T-A-S-S-L-D-(Y/N) (SEQ ID NO: 4). Moreover, as demonstrated inExample 2 of U.S. Pat. No. 6,090,382, the CDR3 domain of the D2E7 heavyand light chains is amenable to substitution with a single alanineresidue (at position 1, 4, 5, 7 or 8 within the VL CDR3 or at position2, 3, 4, 5, 6, 8, 9, 10 or 11 within the VH CDR3) without substantiallyaffecting the K_(off). Still further, the skilled artisan willappreciate that, given the amenability of the D2E7 VL and VH CDR3domains to substitutions by alanine, substitution of other amino acidswithin the CDR3 domains may be possible while still retaining the lowoff rate constant of the antibody, in particular substitutions withconservative amino acids. Preferably, no more than one to fiveconservative amino acid substitutions are made within the D2E7 VL and/orVH CDR3 domains. More preferably, no more than one to three conservativeamino acid substitutions are made within the D2E7 VL and/or VH CDR3domains. Additionally, conservative amino acid substitutions should notbe made at amino acid positions critical for binding to hTNFα. Positions2 and 5 of the D2E7 VL CDR3 and positions 1 and 7 of the D2E7 VH CDR3appear to be critical for interaction with hTNFα and thus, conservativeamino acid substitutions preferably are not made at these positions(although an alanine substitution at position 5 of the D2E7 VL CDR3 isacceptable, as described above) (see U.S. Pat. No. 6,090,382).

Accordingly, in another embodiment, the antibody or antigen-bindingportion thereof preferably contains the following characteristics:

a) dissociates from human TNFα with a K_(off) rate constant of 1×10⁻³s⁻¹ or less, as determined by surface plasmon resonance;

b) has a light chain CDR3 domain comprising the amino acid sequence ofSEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alaninesubstitution at position 1, 4, 5, 7 or 8 or by one to five conservativeamino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9;

c) has a heavy chain CDR3 domain comprising the amino acid sequence ofSEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alaninesubstitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or by one to fiveconservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9,10, 11 and/or 12.

More preferably, the antibody, or antigen-binding portion thereof,dissociates from human TNFα with a K_(off) of 5×10⁻⁴ s⁻¹ or less. Evenmore preferably, the antibody, or antigen-binding portion thereof,dissociates from human TNFα with a K_(off) of 1×10⁻⁴ s⁻¹ or less.

In yet another embodiment, the antibody or antigen-binding portionthereof preferably contains a light chain variable region (LCVR) havinga CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, ormodified from SEQ ID NO: 3 by a single alanine substitution at position1, 4, 5, 7 or 8, and with a heavy chain variable region (HCVR) having aCDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, ormodified from SEQ ID NO: 4 by a single alanine substitution at position2, 3, 4, 5, 6, 8, 9, 10 or 11. Preferably, the LCVR further has a CDR2domain comprising the amino acid sequence of SEQ ID NO: 5 (i.e., theD2E7 VL CDR2) and the HCVR further has a CDR2 domain comprising theamino acid sequence of SEQ ID NO: 6 (i.e., the D2E7 VH CDR2). Even morepreferably, the LCVR further has CDR1 domain comprising the amino acidsequence of SEQ ID NO: 7 (i.e., the D2E7 VL CDR1) and the HCVR has aCDR1 domain comprising the amino acid sequence of SEQ ID NO: 8 (i.e.,the D2E7 VH CDR1). The framework regions for VL preferably are from theV_(κ)I human germline family, more preferably from the A20 humangermline Vk gene and most preferably from the D2E7 VL frameworksequences shown in FIGS. 1A and 1B of U.S. Pat. No. 6,090,382. Theframework regions for VH preferably are from the V_(H)3 human germlinefamily, more preferably from the DP-31 human germline VH gene and mostpreferably from the D2E7 VH framework sequences shown in FIGS. 2A and 2Bof U.S. Pat. No. 6,090,382.

Accordingly, in another embodiment, the antibody or antigen-bindingportion thereof preferably contains a light chain variable region (LCVR)comprising the amino acid sequence of SEQ ID NO: 1 (i.e., the D2E7 VL)and a heavy chain variable region (HCVR) comprising the amino acidsequence of SEQ ID NO: 2 (i.e., the D2E7 VH). In certain embodiments,the antibody comprises a heavy chain constant region, such as an IgG1,IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region. Preferably, theheavy chain constant region is an IgG1 heavy chain constant region or anIgG4 heavy chain constant region. Furthermore, the antibody can comprisea light chain constant region, either a kappa light chain constantregion or a lambda light chain constant region. Preferably, the antibodycomprises a kappa light chain constant region. Alternatively, theantibody portion can be, for example, a Fab fragment or a single chainFv fragment.

In still other embodiments, the invention includes uses of an isolatedhuman antibody, or an antigen-binding portions thereof, containingD2E7-related VL and VH CDR3 domains. For example, antibodies, orantigen-binding portions thereof, with a light chain variable region(LCVR) having a CDR3 domain comprising an amino acid sequence selectedfrom the group consisting of SEQ ID NO: 3, SEQ ID NO: 11, SEQ ID NO: 12,SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO:17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ IDNO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25 and SEQ ID NO: 26 orwith a heavy chain variable region (HCVR) having a CDR3 domaincomprising an amino acid sequence selected from the group consisting ofSEQ ID NO: 4, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO:30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 and SEQID NO: 35.

The TNFα antibody used in the methods and compositions of the inventionmay be modified for improved treatment of Crohn's disease. In someembodiments, the TNFα antibody or antigen binding fragments thereof, ischemically modified to provide a desired effect. For example, pegylationof antibodies and antibody fragments of the invention may be carried outby any of the pegylation reactions known in the art, as described, forexample, in the following references: Focus on Growth Factors 3:4-10(1992); EP 0 154 316; and EP 0 401 384 (each of which is incorporated byreference herein in its entirety). Preferably, the pegylation is carriedout via an acylation reaction or an alkylation reaction with a reactivepolyethylene glycol molecule (or an analogous reactive water-solublepolymer). A preferred water-soluble polymer for pegylation of theantibodies and antibody fragments of the invention is polyethyleneglycol (PEG). As used herein, “polyethylene glycol” is meant toencompass any of the forms of PEG that have been used to derivatizeother proteins, such as mono (Cl—ClO) alkoxy- or aryloxy-polyethyleneglycol.

Methods for preparing pegylated antibodies and antibody fragments of theinvention will generally comprise the steps of (a) reacting the antibodyor antibody fragment with polyethylene glycol, such as a reactive esteror aldehyde derivative of PEG, under conditions whereby the antibody orantibody fragment becomes attached to one or more PEG groups, and (b)obtaining the reaction products. It will be apparent to one of ordinaryskill in the art to select the optimal reaction conditions or theacylation reactions based on known parameters and the desired result.

Pegylated antibodies and antibody fragments may generally be used totreat Crohn's disease by administration of the TNFα antibodies andantibody fragments described herein. Generally the pegylated antibodiesand antibody fragments have increased half-life, as compared to thenonpegylated antibodies and antibody fragments. The pegylated antibodiesand antibody fragments may be employed alone, together, or incombination with other pharmaceutical compositions.

In yet another embodiment of the invention, TNFα antibodies or fragmentsthereof can be altered wherein the constant region of the antibody ismodified to reduce at least one constant region-mediated biologicaleffector function relative to an unmodified antibody. To modify anantibody of the invention such that it exhibits reduced binding to theFc receptor, the immunoglobulin constant region segment of the antibodycan be mutated at particular regions necessary for Fc receptor (FcR)interactions (see e.g., Canfield, S. M. and S. L. Morrison (1991) J.Exp. Med. 173:1483-1491; and Lund, J. et al. (1991) J. of Immunol.147:2657-2662). Reduction in FcR binding ability of the antibody mayalso reduce other effector functions which rely on FcR interactions,such as opsonization and phagocytosis and antigen-dependent cellularcytotoxicity.

An antibody or antibody portion used in the methods of the invention canbe derivatized or linked to another functional molecule (e.g., anotherpeptide or protein). Accordingly, the antibodies and antibody portionsof the invention are intended to include derivatized and otherwisemodified forms of the human anti-hTNFα antibodies described herein,including immunoadhesion molecules. For example, an antibody or antibodyportion of the invention can be functionally linked (by chemicalcoupling, genetic fusion, noncovalent association or otherwise) to oneor more other molecular entities, such as another antibody (e.g., abispecific antibody or a diabody), a detectable agent, a cytotoxicagent, a pharmaceutical agent, and/or a protein or peptide that canmediate associate of the antibody or antibody portion with anothermolecule (such as a streptavidin core region or a polyhistidine tag).

One type of derivatized antibody is produced by crosslinking two or moreantibodies (of the same type or of different types, e.g., to createbispecific antibodies). Suitable crosslinkers include those that areheterobifunctional, having two distinctly reactive groups separated byan appropriate spacer (e.g., m-maleimidobenzoyl-N-hydroxysuccinimideester) or homobifunctional (e.g., disuccinimidyl suberate). Such linkersare available from Pierce Chemical Company, Rockford, Ill.

Useful detectable agents with which an antibody or antibody portion ofthe invention may be derivatized include fluorescent compounds.Exemplary fluorescent detectable agents include fluorescein, fluoresceinisothiocyanate, rhodamine, 5-dimethylamine-1-naphthalenesulfonylchloride, phycoerythrin and the like. An antibody may also bederivatized with detectable enzymes, such as alkaline phosphatase,horseradish peroxidase, glucose oxidase and the like. When an antibodyis derivatized with a detectable enzyme, it is detected by addingadditional reagents that the enzyme uses to produce a detectablereaction product. For example, when the detectable agent horseradishperoxidase is present, the addition of hydrogen peroxide anddiaminobenzidine leads to a colored reaction product, which isdetectable. An antibody may also be derivatized with biotin, anddetected through indirect measurement of avidin or streptavidin binding.

An antibody, or antibody portion, used in the methods and compositionsof the invention, can be prepared by recombinant expression ofimmunoglobulin light and heavy chain genes in a host cell. To express anantibody recombinantly, a host cell is transfected with one or morerecombinant expression vectors carrying DNA fragments encoding theimmunoglobulin light and heavy chains of the antibody such that thelight and heavy chains are expressed in the host cell and, preferably,secreted into the medium in which the host cells are cultured, fromwhich medium the antibodies can be recovered. Standard recombinant DNAmethodologies are used to obtain antibody heavy and light chain genes,incorporate these genes into recombinant expression vectors andintroduce the vectors into host cells, such as those described inSambrook, Fritsch and Maniatis (eds), Molecular Cloning; A LaboratoryManual, Second Edition, Cold Spring Harbor, N.Y., (1989), Ausubel, F. M.et al. (eds.) Current Protocols in Molecular Biology, Greene PublishingAssociates, (1989) and in U.S. Pat. No. 4,816,397 by Boss et al.

To express adalimumab (D2E7) or an adalimumab (D2E7)-related antibody,DNA fragments encoding the light and heavy chain variable regions arefirst obtained. These DNAs can be obtained by amplification andmodification of germline light and heavy chain variable sequences usingthe polymerase chain reaction (PCR). Germline DNA sequences for humanheavy and light chain variable region genes are known in the art (seee.g., the “Vbase” human germline sequence database; see also Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest, FifthEdition, U.S. Department of Health and Human Services, NIH PublicationNo. 91-3242; Tomlinson, I. M., et al. (1992) “The Repertoire of HumanGermline V_(H) Sequences Reveals about Fifty Groups of V_(H) Segmentswith Different Hypervariable Loops” J. Mol. Biol. 227:776-798; and Cox,J. P. L. et al. (1994) “A Directory of Human Germ-line V₇₈ SegmentsReveals a Strong Bias in their Usage” Eur. J. Immunol. 24:827-836; thecontents of each of which are expressly incorporated herein byreference). To obtain a DNA fragment encoding the heavy chain variableregion of D2E7, or a D2E7-related antibody, a member of the V_(H)3family of human germline VH genes is amplified by standard PCR. Mostpreferably, the DP-31 VH germline sequence is amplified. To obtain a DNAfragment encoding the light chain variable region of D2E7, or aD2E7-related antibody, a member of the V_(κ)I family of human germlineVL genes is amplified by standard PCR. Most preferably, the A20 VLgermline sequence is amplified. PCR primers suitable for use inamplifying the DP-31 germline VH and A20 germline VL sequences can bedesigned based on the nucleotide sequences disclosed in the referencescited supra, using standard methods.

Once the germline VH and VL fragments are obtained, these sequences canbe mutated to encode the D2E7 or D2E7-related amino acid sequencesdisclosed herein. The amino acid sequences encoded by the germline VHand VL DNA sequences are first compared to the D2E7 or D2E7-related VHand VL amino acid sequences to identify amino acid residues in the D2E7or D2E7-related sequence that differ from germline. Then, theappropriate nucleotides of the germline DNA sequences are mutated suchthat the mutated germline sequence encodes the D2E7 or D2E7-relatedamino acid sequence, using the genetic code to determine whichnucleotide changes should be made. Mutagenesis of the germline sequencesis carried out by standard methods, such as PCR-mediated mutagenesis (inwhich the mutated nucleotides are incorporated into the PCR primers suchthat the PCR product contains the mutations) or site-directedmutagenesis.

Moreover, it should be noted that if the “germline” sequences obtainedby PCR amplification encode amino acid differences in the frameworkregions from the true germline configuration (i.e., differences in theamplified sequence as compared to the true germline sequence, forexample as a result of somatic mutation), it may be desirable to changethese amino acid differences back to the true germline sequences (i.e.,“backmutation” of framework residues to the germline configuration).

Once DNA fragments encoding D2E7 or D2E7-related VH and VL segments areobtained (by amplification and mutagenesis of germline VH and VL genes,as described above), these DNA fragments can be further manipulated bystandard recombinant DNA techniques, for example to convert the variableregion genes to full-length antibody chain genes, to Fab fragment genesor to a scFv gene. In these manipulations, a VL- or VH-encoding DNAfragment is operatively linked to another DNA fragment encoding anotherprotein, such as an antibody constant region or a flexible linker. Theterm “operatively linked”, as used in this context, is intended to meanthat the two DNA fragments are joined such that the amino acid sequencesencoded by the two DNA fragments remain in-frame.

The isolated DNA encoding the VH region can be converted to afull-length heavy chain gene by operatively linking the VH-encoding DNAto another DNA molecule encoding heavy chain constant regions (CH1, CH2and CH3). The sequences of human heavy chain constant region genes areknown in the art (see e.g., Kabat, E. A., et al. (1991) Sequences ofProteins of Immunological Interest, Fifth Edition, U.S. Department ofHealth and Human Services, NIH Publication No. 91-3242) and DNAfragments encompassing these regions can be obtained by standard PCRamplification. The heavy chain constant region can be an IgG1, IgG2,IgG3, IgG4, IgA, IgE, IgM or IgD constant region, but most preferably isan IgG1 or IgG4 constant region. For a Fab fragment heavy chain gene,the VH-encoding DNA can be operatively linked to another DNA moleculeencoding only the heavy chain CH1 constant region.

The isolated DNA encoding the VL region can be converted to afull-length light chain gene (as well as a Fab light chain gene) byoperatively linking the VL-encoding DNA to another DNA molecule encodingthe light chain constant region, CL. The sequences of human light chainconstant region genes are known in the art (see e.g., Kabat, E. A., etal. (1991) Sequences of Proteins of Immunological Interest, FifthEdition, U.S. Department of Health and Human Services, NIH PublicationNo. 91-3242) and DNA fragments encompassing these regions can beobtained by standard PCR amplification. The light chain constant regioncan be a kappa or lambda constant region, but most preferably is a kappaconstant region.

To create a scFv gene, the VH- and VL-encoding DNA fragments areoperatively linked to another fragment encoding a flexible linker, e.g.,encoding the amino acid sequence (Gly₄-Ser)₃, such that the VH and VLsequences can be expressed as a contiguous single-chain protein, withthe VL and VH regions joined by the flexible linker (see e.g., Bird etal. (1988) Science 242:423-426; Huston et al. (1988) Proc. Natl. Acad.Sci. USA 85:5879-5883; McCafferty et al., Nature (1990) 348:552-554).

To express the antibodies, or antibody portions used in the invention,DNAs encoding partial or full-length light and heavy chains, obtained asdescribed above, are inserted into expression vectors such that thegenes are operatively linked to transcriptional and translationalcontrol sequences. In this context, the term “operatively linked” isintended to mean that an antibody gene is ligated into a vector suchthat transcriptional and translational control sequences within thevector serve their intended function of regulating the transcription andtranslation of the antibody gene. The expression vector and expressioncontrol sequences are chosen to be compatible with the expression hostcell used. The antibody light chain gene and the antibody heavy chaingene can be inserted into separate vector or, more typically, both genesare inserted into the same expression vector. The antibody genes areinserted into the expression vector by standard methods (e.g., ligationof complementary restriction sites on the antibody gene fragment andvector, or blunt end ligation if no restriction sites are present).Prior to insertion of the D2E7 or D2E7-related light or heavy chainsequences, the expression vector may already carry antibody constantregion sequences. For example, one approach to converting the D2E7 orD2E7-related VH and VL sequences to full-length antibody genes is toinsert them into expression vectors already encoding heavy chainconstant and light chain constant regions, respectively, such that theVH segment is operatively linked to the CH segment(s) within the vectorand the VL segment is operatively linked to the CL segment within thevector. Additionally or alternatively, the recombinant expression vectorcan encode a signal peptide that facilitates secretion of the antibodychain from a host cell. The antibody chain gene can be cloned into thevector such that the signal peptide is linked in-frame to the aminoterminus of the antibody chain gene. The signal peptide can be animmunoglobulin signal peptide or a heterologous signal peptide (i.e., asignal peptide from a non-immunoglobulin protein).

In addition to the antibody chain genes, the recombinant expressionvectors of the invention carry regulatory sequences that control theexpression of the antibody chain genes in a host cell. The term“regulatory sequence” is intended to include promoters, enhancers andother expression control elements (e.g., polyadenylation signals) thatcontrol the transcription or translation of the antibody chain genes.Such regulatory sequences are described, for example, in Goeddel; GeneExpression Technology: Methods in Enzymology 185, Academic Press, SanDiego, Calif. (1990). It will be appreciated by those skilled in the artthat the design of the expression vector, including the selection ofregulatory sequences may depend on such factors as the choice of thehost cell to be transformed, the level of expression of protein desired,etc. Preferred regulatory sequences for mammalian host cell expressioninclude viral elements that direct high levels of protein expression inmammalian cells, such as promoters and/or enhancers derived fromcytomegalovirus (CMV) (such as the CMV promoter/enhancer), Simian Virus40 (SV40) (such as the SV40 promoter/enhancer), adenovirus, (e.g., theadenovirus major late promoter (AdMLP)) and polyoma. For furtherdescription of viral regulatory elements, and sequences thereof, seee.g., U.S. Pat. No. 5,168,062 by Stinski, U.S. Pat. No. 4,510,245 byBell et al. and U.S. Pat. No. 4,968,615 by Schaffner et al.

In addition to the antibody chain genes and regulatory sequences, therecombinant expression vectors used in the invention may carryadditional sequences, such as sequences that regulate replication of thevector in host cells (e.g., origins of replication) and selectablemarker genes. The selectable marker gene facilitates selection of hostcells into which the vector has been introduced (see e.g., U.S. Pat.Nos. 4,399,216, 4,634,665 and 5,179,017, all by Axel et al.). Forexample, typically the selectable marker gene confers resistance todrugs, such as G418, hygromycin or methotrexate, on a host cell intowhich the vector has been introduced. Preferred selectable marker genesinclude the dihydrofolate reductase (DHFR) gene (for use in dhfr⁻ hostcells with methotrexate selection/amplification) and the neo gene (forG418 selection).

For expression of the light and heavy chains, the expression vector(s)encoding the heavy and light chains is transfected into a host cell bystandard techniques. The various forms of the term “transfection” areintended to encompass a wide variety of techniques commonly used for theintroduction of exogenous DNA into a prokaryotic or eukaryotic hostcell, e.g., electroporation, calcium-phosphate precipitation,DEAE-dextran transfection and the like. Although it is theoreticallypossible to express the antibodies of the invention in eitherprokaryotic or eukaryotic host cells, expression of antibodies ineukaryotic cells, and most preferably mammalian host cells, is the mostpreferred because such eukaryotic cells, and in particular mammaliancells, are more likely than prokaryotic cells to assemble and secrete aproperly folded and immunologically active antibody. Prokaryoticexpression of antibody genes has been reported to be ineffective forproduction of high yields of active antibody (Boss, M. A. and Wood, C.R. (1985) Immunology Today 6:12-13).

Preferred mammalian host cells for expressing the recombinant antibodiesof the invention include Chinese Hamster Ovary (CHO cells) (includingdhfr-CHO cells, described in Urlaub and Chasin, (1980) Proc. Natl. Acad.Sci. USA 77:4216-4220, used with a DHFR selectable marker, e.g., asdescribed in R. J. Kaufman and P. A. Sharp (1982) Mol. Biol.159:601-621), NSO myeloma cells, COS cells and SP2 cells. Whenrecombinant expression vectors encoding antibody genes are introducedinto mammalian host cells, the antibodies are produced by culturing thehost cells for a period of time sufficient to allow for expression ofthe antibody in the host cells or, more preferably, secretion of theantibody into the culture medium in which the host cells are grown.Antibodies can be recovered from the culture medium using standardprotein purification methods.

Host cells can also be used to produce portions of intact antibodies,such as Fab fragments or scFv molecules. It is understood thatvariations on the above procedure are within the scope of the presentinvention. For example, it may be desirable to transfect a host cellwith DNA encoding either the light chain or the heavy chain (but notboth) of an antibody of this invention. Recombinant DNA technology mayalso be used to remove some or all of the DNA encoding either or both ofthe light and heavy chains that is not necessary for binding to hTNFα.The molecules expressed from such truncated DNA molecules are alsoencompassed by the antibodies of the invention. In addition,bifunctional antibodies may be produced in which one heavy and one lightchain are an antibody of the invention and the other heavy and lightchain are specific for an antigen other than hTNFα by crosslinking anantibody of the invention to a second antibody by standard chemicalcrosslinking methods.

In a preferred system for recombinant expression of an antibody, orantigen-binding portion thereof, of the invention, a recombinantexpression vector encoding both the antibody heavy chain and theantibody light chain is introduced into dhfr-CHO cells by calciumphosphate-mediated transfection. Within the recombinant expressionvector, the antibody heavy and light chain genes are each operativelylinked to CMV enhancer/AdMLP promoter regulatory elements to drive highlevels of transcription of the genes. The recombinant expression vectoralso carries a DHFR gene, which allows for selection of CHO cells thathave been transfected with the vector using methotrexateselection/amplification. The selected transformant host cells areculture to allow for expression of the antibody heavy and light chainsand intact antibody is recovered from the culture medium. Standardmolecular biology techniques are used to prepare the recombinantexpression vector, transfect the host cells, select for transformants,culture the host cells and recover the antibody from the culture medium.

In view of the foregoing, nucleic acid, vector and host cellcompositions that can be used for recombinant expression of theantibodies and antibody portions used in the invention include nucleicacids, and vectors comprising said nucleic acids, comprising the humanTNFα antibody adalimumab (D2E7). The nucleotide sequence encoding theD2E7 light chain variable region is shown in SEQ ID NO: 36. The CDR1domain of the LCVR encompasses nucleotides 70-102, the CDR2 domainencompasses nucleotides 148-168 and the CDR3 domain encompassesnucleotides 265-291. The nucleotide sequence encoding the D2E7 heavychain variable region is shown in SEQ ID NO: 37. The CDR1 domain of theHCVR encompasses nucleotides 91-105, the CDR2 domain encompassesnucleotides 148-198 and the CDR3 domain encompasses nucleotides 295-330.It will be appreciated by the skilled artisan that nucleotide sequencesencoding D2E7-related antibodies, or portions thereof (e.g., a CDRdomain, such as a CDR3 domain), can be derived from the nucleotidesequences encoding the D2E7 LCVR and HCVR using the genetic code andstandard molecular biology techniques.

Recombinant human antibodies of the invention in addition to D2E7 or anantigen binding portion thereof, or D2E7-related antibodies disclosedherein can be isolated by screening of a recombinant combinatorialantibody library, preferably a scFv phage display library, preparedusing human VL and VH cDNAs prepared from mRNA derived from humanlymphocytes. Methodologies for preparing and screening such librariesare known in the art. In addition to commercially available kits forgenerating phage display libraries (e.g., the Pharmacia RecombinantPhage Antibody System, catalog no. 27-9400-01; and the StratageneSurfZAP™ phage display kit, catalog no. 240612), examples of methods andreagents particularly amenable for use in generating and screeningantibody display libraries can be found in, for example, Ladner et al.U.S. Pat. No. 5,223,409; Kang et al. PCT Publication No. WO 92/18619;Dower et al. PCT Publication No. WO 91/17271; Winter et al. PCTPublication No. WO 92/20791; Markland et al. PCT Publication No. WO92/15679; Breitling et al. PCT Publication No. WO 93/01288; McCaffertyet al. PCT Publication No. WO 92/01047; Garrard et al. PCT PublicationNo. WO 92/09690; Fuchs et al. (1991) Bio/Technology 9:1370-1372; Hay etal. (1992) Hum Antibod Hybridomas 3:81-65; Huse et al. (1989) Science246:1275-1281; McCafferty et al., Nature (1990) 348:552-554; Griffithset al. (1993) EMBO J 12:725-734; Hawkins et al. (1992)J Mol Biol226:889-896; Clackson et al. (1991) Nature 352:624-628; Gram et al.(1992) PNAS 89:3576-3580; Garrard et al. (1991) Bio/Technology9:1373-1377; Hoogenboom et al. (1991) Nuc Acid Res 19:4133-4137; andBarbas et al. (1991) PNAS 88:7978-7982.

In a preferred embodiment, to isolate human antibodies with highaffinity and a low off rate constant for hTNFα, a murine anti-hTNFαantibody having high affinity and a low off rate constant for hTNFα(e.g., MAK 195, the hybridoma for which has deposit number ECACC 87050801) is first used to select human heavy and light chain sequenceshaving similar binding activity toward hTNFα, using the epitopeimprinting methods described in Hoogenboom et al., PCT Publication No.WO 93/06213. The antibody libraries used in this method are preferablyscFv libraries prepared and screened as described in McCafferty et al.,PCT Publication No. WO 92/01047, McCafferty et al., Nature (1990)348:552-554; and Griffiths et al., (1993) EMBO J 12:725-734. The scFvantibody libraries preferably are screened using recombinant human TNFαas the antigen.

Once initial human VL and VH segments are selected, “mix and match”experiments, in which different pairs of the initially selected VL andVH segments are screened for hTNFα binding, are performed to selectpreferred VL/VH pair combinations. Additionally, to further improve theaffinity and/or lower the off rate constant for hTNFα binding, the VLand VH segments of the preferred VL/VH pair(s) can be randomly mutated,preferably within the CDR3 region of VH and/or VL, in a processanalogous to the in vivo somatic mutation process responsible foraffinity maturation of antibodies during a natural immune response. Thisin vitro affinity maturation can be accomplished by amplifying VH and VLregions using PCR primers complimentary to the VH CDR3 or VL CDR3,respectively, which primers have been “spiked” with a random mixture ofthe four nucleotide bases at certain positions such that the resultantPCR products encode VH and VL segments into which random mutations havebeen introduced into the VH and/or VL CDR3 regions. These randomlymutated VH and VL segments can be rescreened for binding to hTNFα andsequences that exhibit high affinity and a low off rate for hTNFαbinding can be selected.

Following screening and isolation of an anti-hTNFα antibody of theinvention from a recombinant immunoglobulin display library, nucleicacid encoding the selected antibody can be recovered from the displaypackage (e.g., from the phage genome) and subcloned into otherexpression vectors by standard recombinant DNA techniques. If desired,the nucleic acid can be further manipulated to create other antibodyforms of the invention (e.g., linked to nucleic acid encoding additionalimmunoglobulin domains, such as additional constant regions). To expressa recombinant human antibody isolated by screening of a combinatoriallibrary, the DNA encoding the antibody is cloned into a recombinantexpression vector and introduced into a mammalian host cells, asdescribed in further detail in above.

Methods of isolating human neutralizing antibodies with high affinityand a low off rate constant for hTNFα are described in U.S. Pat. Nos.6,090,382, 6,258,562, and 6,509,015, each of which is incorporated byreference herein.

Antibodies, antibody-portions, and other TNFα inhibitors for use in themethods of the invention, can be incorporated into pharmaceuticalcompositions suitable for administration to a subject. Typically, thepharmaceutical composition comprises an antibody, antibody portion, orother TNFα inhibitor, and a pharmaceutically acceptable carrier. As usedherein, “pharmaceutically acceptable carrier” includes any and allsolvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents, and the like that arephysiologically compatible. Examples of pharmaceutically acceptablecarriers include one or more of water, saline, phosphate bufferedsaline, dextrose, glycerol, ethanol and the like, as well ascombinations thereof. In many cases, it is preferable to includeisotonic agents, for example, sugars, polyalcohols such as mannitol,sorbitol, or sodium chloride in the composition. Pharmaceuticallyacceptable carriers may further comprise minor amounts of auxiliarysubstances such as wetting or emulsifying agents, preservatives orbuffers, which enhance the shelf life or effectiveness of the antibody,antibody portion, or other TNFα inhibitor.

The compositions for use in the methods and compositions of theinvention may be in a variety of forms. These include, for example,liquid, semi-solid and solid dosage forms, such as liquid solutions(e.g., injectable and infusible solutions), dispersions or suspensions,tablets, pills, powders, liposomes and suppositories. The preferred formdepends on the intended mode of administration and therapeuticapplication. Typical preferred compositions are in the form ofinjectable or infusible solutions, such as compositions similar to thoseused for passive immunization of humans with other antibodies or otherTNFα inhibitors. The preferred mode of administration is parenteral(e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In apreferred embodiment, the antibody or other TNFα inhibitor isadministered by intravenous infusion or injection. In another preferredembodiment, the antibody or other TNFα inhibitor is administered byintramuscular or subcutaneous injection.

Therapeutic compositions typically must be sterile and stable under theconditions of manufacture and storage. The composition can be formulatedas a solution, microemulsion, dispersion, liposome, or other orderedstructure suitable to high drug concentration. Sterile injectablesolutions can be prepared by incorporating the active compound (i.e.,antibody, antibody portion, or other TNFα inhibitor) in the requiredamount in an appropriate solvent with one or a combination ofingredients enumerated above, as required, followed by filteredsterilization. Generally, dispersions are prepared by incorporating theactive compound into a sterile vehicle that contains a basic dispersionmedium and the required other ingredients from those enumerated above.In the case of sterile powders for the preparation of sterile injectablesolutions, the preferred methods of preparation are vacuum drying andfreeze-drying that yields a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof. The proper fluidity of a solution can be maintained,for example, by the use of a coating such as lecithin, by themaintenance of the required particle size in the case of dispersion andby the use of surfactants. Prolonged absorption of injectablecompositions can be brought about by including in the composition anagent that delays absorption, for example, monostearate salts andgelatin.

In one embodiment, the invention includes pharmaceutical compositionscomprising an effective TNFα inhibitor and a pharmaceutically acceptablecarrier, wherein the effective TNFα inhibitor may be used to treatCrohn's disease.

In one embodiment, the antibody or antibody portion for use in themethods of the invention is incorporated into a pharmaceuticalformulation as described in PCT/IB03/04502 and U.S. Appln. No.20040033228, incorporated by reference herein. This formulation includesa concentration 50 mg/ml of the antibody D2E7 (adalimumab), wherein onepre-filled syringe contains 40 mg of antibody for subcutaneousinjection.

The antibodies, antibody-portions, and other TNFα inhibitors of thepresent invention can be administered by a variety of methods known inthe art, although for many therapeutic applications, the preferredroute/mode of administration is parenteral, e.g., subcutaneousinjection. In another embodiment, administration is via intravenousinjection or infusion.

As will be appreciated by the skilled artisan, the route and/or mode ofadministration will vary depending upon the desired results. In certainembodiments, the active compound may be prepared with a carrier thatwill protect the compound against rapid release, such as a controlledrelease formulation, including implants, transdermal patches, andmicroencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Manymethods for the preparation of such formulations are patented orgenerally known to those skilled in the art. See, e.g., Sustained andControlled Release Drug Delivery Systems, Robinson, ed., Dekker, Inc.,New York, 1978.

In one embodiment, the TNFα antibodies and inhibitors used in theinvention are delivered to a subject subcutaneously. In one embodiment,the subject administers the TNFα inhibitor, including, but not limitedto, TNFα antibody, or antigen-binding portion thereof, tohimself/herself.

The TNFα antibodies and inhibitors used in the invention may also beadministered in the form of protein crystal formulations which include acombination of protein crystals encapsulated within a polymeric carrierto form coated particles. The coated particles of the protein crystalformulation may have a spherical morphology and be microspheres of up to500 micro meters in diameter or they may have some other morphology andbe microparticulates. The enhanced concentration of protein crystalsallows the antibody of the invention to be delivered subcutaneously. Inone embodiment, the TNFα antibodies of the invention are delivered via aprotein delivery system, wherein one or more of a protein crystalformulation or composition, is administered to a subject with aTNFα-related disorder. Compositions and methods of preparing stabilizedformulations of whole antibody crystals or antibody fragment crystalsare also described in WO 02/072636, which is incorporated by referenceherein. In one embodiment, a formulation comprising the crystallizedantibody fragments described in PCT/IB03/04502 and U.S. Appln. No.20040033228, incorporated by reference herein, are used to treatrheumatoid arthritis using the treatment methods of the invention.

In certain embodiments, an antibody, antibody portion, or other TNFαinhibitor of the invention may be orally administered, for example, withan inert diluent or an assimilable edible carrier. The compound (andother ingredients, if desired) may also be enclosed in a hard or softshell gelatin capsule, compressed into tablets, or incorporated directlyinto the subject's diet. For oral therapeutic administration, thecompounds may be incorporated with excipients and used in the form ofingestible tablets, buccal tablets, troches, capsules, elixirs,suspensions, syrups, wafers, and the like. To administer a compound ofthe invention by other than parenteral administration, it may benecessary to coat the compound with, or co-administer the compound with,a material to prevent its inactivation.

Supplementary active compounds can also be incorporated into thecompositions. In certain embodiments, an antibody or antibody portionfor use in the methods of the invention is coformulated with and/orcoadministered with one or more additional therapeutic agents, includingan Crohn's disease inhibitor or antagonist. For example, an anti-hTNFαantibody or antibody portion of the invention may be coformulated and/orcoadministered with one or more additional antibodies that bind othertargets associated with TNFα related disorders (e.g., antibodies thatbind other cytokines or that bind cell surface molecules), one or morecytokines, soluble TNFα receptor (see e.g., PCT Publication No. WO94/06476) and/or one or more chemical agents that inhibit hTNFαproduction or activity (such as cyclohexane-ylidene derivatives asdescribed in PCT Publication No. WO 93/19751) or any combinationthereof. Furthermore, one or more antibodies of the invention may beused in combination with two or more of the foregoing therapeuticagents. Such combination therapies may advantageously utilize lowerdosages of the administered therapeutic agents, thus avoiding possibleside effects, complications or low level of response by the patientassociated with the various monotherapies.

The pharmaceutical compositions of the invention may include a“therapeutically effective amount” or a “prophylactically effectiveamount” of an antibody or antibody portion of the invention. A“therapeutically effective amount” refers to an amount effective, atdosages and for periods of time necessary, to achieve the desiredtherapeutic result. A therapeutically effective amount of the antibody,antibody portion, or other TNFα inhibitor may vary according to factorssuch as the disease state, age, sex, and weight of the individual, andthe ability of the antibody, antibody portion, other TNFα inhibitor toelicit a desired response in the individual. A therapeutically effectiveamount is also one in which any toxic or detrimental effects of theantibody, antibody portion, or other TNFα inhibitor are outweighed bythe therapeutically beneficial effects. A “prophylactically effectiveamount” refers to an amount effective, at dosages and for periods oftime necessary, to achieve the desired prophylactic result. Typically,since a prophylactic dose is used in subjects prior to or at an earlierstage of disease, the prophylactically effective amount will be lessthan the therapeutically effective amount.

Additional description regarding methods and uses of the inventioncomprising administration of a TNFα inhibitor are described in Part IIIof this specification.

The invention also pertains to packaged pharmaceutical compositions orkits for administering the anti-TNF antibodies of the invention for thetreatment of Crohn's disease. In one embodiment of the invention, thekit comprises a TNFα inhibitor, such as an antibody and instructions foradministration of the TNFα inhibitor for treatment of Crohn's disease.The instructions may describe how, e.g., subcutaneously, and when, e.g.,at week 0, week 2, week 4, etc., the different doses of TNFα inhibitorshall be administered to a subject for treatment.

Another aspect of the invention pertains to kits containing apharmaceutical composition comprising a TNFα inhibitor, such as anantibody, and a pharmaceutically acceptable carrier and one or morepharmaceutical compositions each comprising an additional therapeuticagent useful for treating Crohn's disease, and a pharmaceuticallyacceptable carrier. Alternatively, the kit comprises a singlepharmaceutical composition comprising an anti-TNFα antibody, one or moredrugs useful for treating Crohn's disease, and a pharmaceuticallyacceptable carrier. The instructions may describe how, e.g.,subcutaneously, and when, e.g., at week 0, week 2, week 4, etc., thedifferent doses of TNFα inhibitor and/or the additional therapeuticagent shall be administered to a subject for treatment.

The kit may contain instructions for dosing of the pharmaceuticalcompositions for the treatment of Crohn's disease. Additionaldescription regarding articles of manufacture of the invention aredescribed in subsection III.

The package or kit alternatively can contain the TNFα inhibitor and itcan be promoted for use, either within the package or throughaccompanying information, for the uses or treatment of the disordersdescribed herein. The packaged pharmaceuticals or kits further caninclude a second agent (as described herein) packaged with or copromotedwith instructions for using the second agent with a first agent (asdescribed herein).

III. Uses and Compositions for Treating Psoriatic Arthritis

Tumor necrosis factor has been implicated in the pathophysiology ofpsoriatic arthritis (Partsch et al. (1998) Ann Rheum Dis. 57:691;Ritchlin et al. (1998) J Rheumatol. 25:1544). As referred to herein,psoriatic arthritis (PsA) or psoriasis associated with the skin, refersto chronic inflammatory arthritis which is associated with psoriasis.Psoriasis is a common chronic skin condition that causes red patches onthe body. About 1 in 20 individuals with psoriasis will developarthritis along with the skin condition, and in about 75% of cases,psoriasis precedes the arthritis. PsA exhibits itself in a variety ofways, ranging from mild to severe arthritis, wherein the arthritisusually affects the fingers and the spine. When the spine is affected,the symptoms are similar to those of ankylosing spondylitis, asdescribed above. The TNFα antibody, or antigen-binding fragment thereof,of the invention can be used to treat PsA.

Treatment of psoriatic arthritis may be determined according to standardclinical definitions. For example, primary efficacy for signs andsymptoms can be measured via American College of Rheumatologypreliminary criteria for improvement (ACR). ACR criteria measuresimprovement in tender or swollen joint counts and improvement in threeof the following five parameters: acute phase reactant (such assedimentation rate); patient assessment; physician assessment; painscale; and disability/functional questionnaire. ACR criteria isindicated as ACR 20 (a 20 percent improvement in tender or swollen jointcounts as well as 20 percent improvement in three of the other fivecriteria), ACR 50 (a 50 percent improvement in tender or swollen jointcounts as well as 50 percent improvement in three of the other fivecriteria), and ACR 70 (a 70 percent improvement in tender or swollenjoint counts as well as 70 percent improvement in three of the otherfive criteria).

An additional primary endpoint includes evaluation of radiologic changesover 6 to 12 months to assess changes in structural damage. Multipleother evaluations are performed during treatment including PsoriaticArthritis Response Criteria (PsARC), quality of life measurements, andskin evaluations to determine efficacy on psoriasis lesions (psorasisarea severity index (PASI) and target lesion evaluations).

In one embodiment, the invention provides a method for treatingpsoriatic arthritis in a subject comprising administering a human TNFαantibody, or an antigen-binding portion thereof, to the subject, suchthat the psoriatic arthritis is treated. In one embodiment, theinvention describes a use of a human TNFα antibody, or antigen-bindingportion thereof, in the manufacture of a medicament for treatingpsoriatic arthritis in a subject. The medicament may be foradministration to the subject on a maintenance dose regimen. In oneembodiment, efficacy of treatment of psoriatic arthritis is determinedby achievement of an ACR20, ACR50 or ACR70 response, or a PASI50,PASI75, or PASI90 response in the subject.

The TNFα antibody, or an antigen-binding portion thereof, may beadministered to the subject on a biweekly dosing regimen. In oneembodiment, biweekly dosing includes a dosing regimen wherein doses of aTNFα inhibitor are administered to a subject every other week beginningat week 0. In one embodiment, biweekly dosing includes a dosing regimenwhere doses of a TNFα inhibitor are administered to a subject everyother week consecutively for a given time period, e.g., 4 weeks, 8weeks, 16, weeks, 24 weeks, 26 weeks, 32 weeks, 36 weeks, 42 weeks, 48weeks, 52 weeks, 56 weeks, etc.

In one embodiment, treatment of psoriatic arthritis is achieved byadministering a human TNFα antibody, or an antigen-binding portionthereof, to a subject having psoriatic arthritis, wherein the human TNFαantibody, or an antigen-binding portion thereof, is administered on abiweekly dosing regimen. In one embodiment, the human TNFα antibody, oran antigen-binding portion thereof, is administered in a dose of about40 mg. In one embodiment, the human TNFα antibody, or an antigen-bindingportion thereof, is adalimumab.

Methods of treatment described herein may include administration of aTNFα inhibitor to a subject to achieve a therapeutic goal, e.g.,achievement of an ACR20, ACR50, or ACR70 response, or a PASI50, PASI75,or PASI90 response. Also included in the scope of the invention are usesof a TNFα inhibitor in the manufacture of a medicament to achieve atherapeutic goal, e.g., achievement of an ACR20, ACR50, or ACR70response, or a PASI50, PASI75, or PASI90 response. Thus, where methodsare described herein, it is also intended to be part of this inventionthat the use of the TNFα inhibitor in the manufacture of a medicamentfor the purpose of the method is also considered within the scope of theinvention. Likewise, where a use of a TNFα inhibitor in the manufactureof a medicament for the purpose of achieving a therapeutic goal isdescribed, methods of treatment resulting in the therapeutic goal arealso intended to be part of the invention.

In one embodiment, treatment of psoriatic arthritis is achieved byadministering a TNFα inhibitor to a subject in accordance with abiweekly dosing regimen. Biweekly dosing regimens can be used to treatdisorders in which TNFα activity is detrimental, and are furtherdescribed in U.S. application Ser. No. 10/163,657 (US 20030235585),incorporated by reference herein.

In one embodiment, the invention provides a method of treating psoriaticarthritis in a subject comprising administering a human TNFα antibody,or antigen-binding portion thereof, e.g., adalimumab, to the subject atweek 0 on a biweekly dosing regimen. In one embodiment, the human TNFαantibody, or antigen-binding portion thereof, is administeredsubcutaneously. In one embodiment, psoriatic arthritis is treated byadministering a human TNFα antibody, or antigen-binding portion thereof,on biweekly dosing regimen for at least about 12, 24, 36 or 48 weeks.

Dosage unit form as used herein refers to physically discrete unitssuited as unitary dosages for the mammalian subjects to be treated; eachunit containing a predetermined quantity of active compound calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. The specification for the dosage unitforms of the invention are dictated by and directly dependent on (a) theunique characteristics of the active compound and the particulartherapeutic or prophylactic effect to be achieved, and (b) thelimitations inherent in the art of compounding such an active compoundfor the treatment of sensitivity in individuals.

Dosage regimens described herein may be adjusted to provide the optimumdesired response, e.g., maintaining remission of Crohn's disease, inconsideration of the teachings herein. It is to be noted that dosagevalues may vary with the type and severity of Crohn's disease. It is tobe further understood that for any particular subject, specific dosageregimens may be adjusted over time according to the teachings of thespecification and the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions, and that dosage amounts and ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed invention.

Examples of other methods and uses of TNFα inhibitors for the treatmentof psoriatic arthritis are also described in: U.S. provisional patentapplication No. 60/812,312 (BBI-248-1), filed on Jun. 8, 2006; U.S.provisional patent application No. 60/832,370 (BBI-254-1), filed on Jul.20, 2006; and U.S. provisional patent application No. 60/851,830(BBI-260-1), filed on Oct. 12, 2006; each of which is incorporatedherein.

Subpopulations

The invention provides uses and methods for treating certainsubpopulations of psoriatic arthritis patients with a TNFα inhibitor.

The invention provides a method of treating oligoarticular arthritis ina subject comprising administering to the subject a TNFα inhibitor, suchthat oligoarticular arthritis is treated. Subjects having oligoarticulararthritis may be administered a TNFα inhibitor such that oligoarticulararthritis is treated and advancement of the disease is prevented. Theinvention also provides use of a TNFα inhibitor in the manufacture of amedicament for the treatment of oligoarticular arthritis in a subjectwho has oligoarticular arthritis.

The invention also provides a method for treating early and establishedpsoriatic arthritis in a subject, comprising administering to thesubject a TNFα inhibitor, such that early and established psoriaticarthritis are treated. Subjects having early psoriatic arthritis may beadministered a TNFα inhibitor such that the psoriatic arthritis istreated and advancement of the disease is prevented. Subjects havingestablished psoriatic arthritis may be administered a TNFα inhibitorsuch that the psoriatic arthritis is treated and advancement of thedisease is prevented. The invention also provides use of a TNFαinhibitor in the manufacture of a medicament for the treatment of earlyand established psoriatic arthritis in a subject who has either early orestablished psoriatic arthritis.

The invention also provides a method for treating a subpopulation ofpsoriatic arthritis patients who have failed disease modifyinganti-rheumatic drug (DMARDs) therapy, e.g., methotrexate, for thetreatment of psoriatic arthritis. Traditional interventions for moderateto severe PsA have included nonsteroidal anti-inflammatory drugs(NSAIDs) and nonbiologic disease-modifying antirheumatic drugs (DMARDs).A meta-analysis of published, well-controlled studies found that, of thetraditional DMARDs, only high-dosage, parenteral methotrexate (MTX) haddemonstrated efficacy for both skin and articular manifestations of PsA.(Jones et al, Cochrane Database Syst Rev 2000; (3):CD000212. 2000). Ithas not yet been established whether MTX has efficacy against jointdestruction in PsA. In certain instances, some patients who areadministered a DMARD for the treatment of psoriatic arthritis havesubtherapeutic responses to such treatment. In one embodiment, theinvention provides use of a TNFα inhibitor in the manufacture of amedicament for treatment of psoriatic arthritis in a subject who has hada subtherapeutic response to a DMARD.

In one embodiment, the invention provides an article of manufacturecomprising adalimumab and a package insert, wherein the package insertindicates that adalimumab may be used to treat psoriatic arthritis inpatients who have had an inadequate response to conventional DMARDtherapy.

Articles of Manufacture

The invention also provides a packaged pharmaceutical compositionwherein the TNFα inhibitor, e.g., TNFα antibody, is packaged within akit or an article of manufacture. The kit or article of manufacture ofthe invention contains materials useful for the treatment, preventionand/or diagnosis of psoriatic arthritis. The kit or article ofmanufacture comprises a container and a label or package insert orprinted material on or associated with the container which providesinformation regarding use of the TNFα inhibitor, e.g., a TNFα antibody,for the treatment of psoriatic arthritis.

A kit or an article of manufacture refers to a packaged productcomprising components with which to administer a TNFα inhibitor fortreatment of psoriatic arthritis. The kit preferably comprises a box orcontainer that holds the components of the kit. The box or container isaffixed with a label or a Food and Drug Administration approved label,including a protocol for administering the TNFα inhibitor. The box orcontainer holds components of the invention which are preferablycontained within plastic, polyethylene, polypropylene, ethylene, orpropylene vessels. The vessels can be capped-tubes or bottles. The kitcan also include instructions for administering the TNFα antibody of theinvention. In one embodiment the kit of the invention includes theformulation comprising the human antibody adalimumab (or D2E7), asdescribed in PCT/IB03/04502 and U.S. application Ser. No. 10/222,140,incorporated by reference herein.

The term “package insert” is used to refer to instructions customarilyincluded in commercial packages of therapeutic products, that containinformation about the indications, usage, dosage, administration,contraindications and/or warnings concerning the use of such therapeuticproducts.

In one embodiment, the article of manufacture of the invention comprises(a) a first container with a composition contained therein, wherein thecomposition comprises a TNFα antibody; and (b) a package insertindicating that the TNFα antibody may be used for reducing signs andsymptoms and treatment of psoriatic arthritis. In a preferredembodiment, the label or package insert indicates that the TNFαinhibitor, e.g., a TNFα antibody, is used for treatment of psoriaticarthritis.

Suitable containers for the TNFα inhibitor, e.g., a TNFα antibody,include, for example, bottles, vials, syringes, pens, etc. Thecontainers may be formed from a variety of materials such as glass orplastic. The container holds a composition which is by itself or whencombined with another composition effective for treating, preventingand/or diagnosing the condition and may have a sterile access port.

In one embodiment, the article of manufacture comprises a TNFαinhibitor, e.g., a TNFα antibody, and a label which indicates to asubject who will be administering the TNFα inhibitor about using theTNFα inhibitor for the treatment of psoriatic arthritis. The label maybe anywhere within or on the article of manufacture. In one embodiment,the article of manufacture comprises a container, such as a box, whichcomprises the TNFα inhibitor and a package insert or label providinginformation pertaining to use of the TNFα inhibitor for the treatment ofpsoriatic arthritis. In another embodiment, the information is printedon a label which is on the outside of the article of manufacture, in aposition which is visible to prospective purchasers.

In one embodiment, the package insert of the invention informs a reader,including a subject, e.g., a purchaser, who will be administering theTNFα inhibitor for treatment, that the TNFα inhibitor, e.g., a TNFαantibody such as adalimumab, is an indicated treatment of psoriaticarthritis, including of moderately to severely active disease in adultpatients.

In one embodiment, the package insert describes certain patientpopulations who may respond favorably to the TNFα inhibitor within thearticle of manufacture. For example, the package insert may indicatethat the TNFα antibody, e.g., adalimumab, may be used to treat psoriaticarthritis in patients who have had an inadequate response toconventional therapy.

In another embodiment, the label of the invention indicates thatadalimumab is indicated for treatment of early to established psoriaticarthritis in adult patients who have had an inadequate response toconventional therapy. In another embodiment, the label of the inventionindicates that adalimumab is indicated for treatment of oligoarticulararthritis in patients with psoriatic arthritis.

In one embodiment, the package insert of the invention describes certaintherapeutic benefits of the TNFα antibody, e.g., adalimumab, includingspecific symptoms of psoriatic arthritis which may be reduced by usingthe TNFα antibody, e.g., adalimumab. It should be noted that the packageinsert may also contain information pertaining to other disorders whichare treatable using the TNFα antibody, e.g., adalimumab. Informationdescribed herein which is provided in a package insert and pertains toother disorders, i.e., diseases other than psoriatic arthritis, is alsoincluded within the scope of the invention. The package insert of theinvention may indicate that extra TNFα in your body can attack normalhealthy body tissues and cause inflammation especially in the tissues inyour bones, cartilage, joints and digestive tract. The package insert ofthe invention may also indicate that adalimumab helps reduce the signsand symptoms of immune diseases, including rheumatoid and psoriaticarthritis (pain and swollen joints), ankylosing spondylitis (morningstiffness and back pain), and Crohn's disease (abdominal pain anddiarrhea).

In another embodiment, the package insert of the invention describes thedose and administration of adalimumab, for the treatment of psoriaticarthritis. The label may indicate that the initiation of therapyincludes a biweekly 40 mg subcutaneous dose. The label may also indicatethat the maintenance dosing for the treatment of psoriatic arthritiswith adalimumab is 40 mg every other week. In another embodiment, thepackage insert of the invention indicates that adalimumab isadministered by subcutaneous injection.

In another embodiment, the label of the invention indicates that therecommended TNFα inhibitor, e.g., a TNFα antibody such as adalimumab,dose regimen for adult patients with psoriatic arthritis is 40 mg atweek 0, followed by 40 mg every other week.

The package insert of the invention may also provide information tosubjects who will be receiving adalimumab regarding combination uses forboth safety and efficacy purposes. The package insert of the inventionmay contain warnings and precautions regarding the use of the TNFαinhibitor, e.g., a TNFα antibody such as adalimumab.

The label of the invention may contain information regarding the use ofthe TNFα inhibitor, e.g., a TNFα antibody such as adalimumab, inclinical studies for psoriatic arthritis. In one embodiment, the labelof the invention describes the studies described herein as the Examples,either as a whole or in portion.

The label of the invention may contain information regarding thepharmacodynamics of the TNFα inhibitor, e.g., a TNFα antibody such asadalimumab. the label of the invention may contain information regardingthe pharmacokinetics of the TNFα inhibitor, e.g., a TNFα antibody suchas adalimumab.

In one embodiment of the invention, the kit comprises a TNFα inhibitor,such as an antibody, an second pharmaceutical composition comprising anadditional therapeutic agent, and instructions for administration ofboth agents for the treatment of psoriatic arthritis. The instructionsmay describe how, e.g., subcutaneously, and when, e.g., at week 0, week2, and biweekly thereafter, doses of TNFα antibody and/or the additionaltherapeutic agent shall be administered to a subject for treatment.

Another aspect of the invention pertains to kits containing apharmaceutical composition comprising an anti-TNFα antibody and apharmaceutically acceptable carrier and one or more additionalpharmaceutical compositions each comprising a drug useful for treating aTNFα related disorder and a pharmaceutically acceptable carrier.Alternatively, the kit comprises a single pharmaceutical compositioncomprising an anti-TNFα antibody, one or more drugs useful for treatinga TNFα related disorder and a pharmaceutically acceptable carrier. Thekits further contain instructions for dosing of the pharmaceuticalcompositions for the treatment of a TNFα related disorder.

The package or kit alternatively may contain the TNFα inhibitor and itmay be promoted for use, either within the package or throughaccompanying information, for the uses or treatment of the disordersdescribed herein. The packaged pharmaceuticals or kits further caninclude a second agent (as described herein) packaged with or copromotedwith instructions for using the second agent with a first agent (asdescribed herein).

Additional Therapeutic Agents

Antibodies of the invention, or antigen binding portions thereof can beused alone or in combination to treat such diseases. It should beunderstood that the antibodies of the invention or antigen bindingportion thereof can be used alone or in combination with an additionalagent, e.g., a therapeutic agent, said additional agent being selectedby the skilled artisan for its intended purpose. For example, theadditional agent can be a therapeutic agent art-recognized as beinguseful to treat the disease or condition being treated by the antibodyof the present invention. The additional agent also can be an agent thatimparts a beneficial attribute to the therapeutic composition e.g., anagent which effects the viscosity of the composition.

It should further be understood that the combinations which are to beincluded within this invention are those combinations useful for theirintended purpose. The agents set forth below are illustrative forpurposes and not intended to be limited. The combinations, which arepart of this invention, can be the antibodies of the present inventionand at least one additional agent selected from the lists below. Thecombination can also include more than one additional agent, e.g., twoor three additional agents if the combination is such that the formedcomposition can perform its intended function.

Binding proteins described herein may be used in combination withadditional therapeutic agents such as a Disease Modifying Anti-RheumaticDrug (DMARD) or a Nonsteroidal Antiinflammatory Drug (NSAID) or asteroid or any combination thereof. Preferred examples of a DMARD arehydroxychloroquine, leflunomide, methotrexate, parenteral gold, oralgold and sulfasalazine. Preferred examples of non-steroidalanti-inflammatory drug(s) also referred to as NSAIDS include drugs likeibuprofen. Other preferred combinations are corticosteroids includingprednisolone; the well known side effects of steroid use can be reducedor even eliminated by tapering the steroid dose required when treatingpatients in combination with the antibodies of this invention.Antibodies of the invention, or antigen binding portions thereof, can becombined with antibodies to cell surface molecules such as CD2, CD3,CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2),CD90, CTLA or their ligands including CD154 (gp39 or CD40L).

Preferred combinations of therapeutic agents may interfere at differentpoints in the autoimmune and subsequent inflammatory cascade; preferredexamples include TNF antagonists such as soluble p55 or p75 TNFreceptors, derivatives, thereof, (p75TNFR1gG (Enbrel™) or p55TNFR1gG(Lenercept), chimeric, humanized or human TNF antibodies, or a fragmentthereof, including infliximab (Remicade®, Johnson and Johnson; describedin U.S. Pat. No. 5,656,272, incorporated by reference herein), CDP571 (ahumanized monoclonal anti-TNF-alpha IgG4 antibody), CDP 870 (a humanizedmonoclonal anti-TNF-alpha antibody fragment), an anti-TNF dAb (Peptech),CNTO 148 (golimumab; Medarex and Centocor, see WO 02/12502), andadalimumab (Humira® Abbott Laboratories, a human anti-TNF mAb, describedin U.S. Pat. No. 6,090,382 as D2E7). Additional TNF antibodies which canbe used in the invention are described in U.S. Pat. Nos. 6,593,458;6,498,237; 6,451,983; and 6,448,380, each of which is incorporated byreference herein. Other combinations including TNFα converting enzyme(TACE) inhibitors; IL-1 inhibitors (Interleukin-1-converting enzymeinhibitors, IL-1RA etc.) may be effective for the same reason. Otherpreferred combinations include Interleukin 11. Yet another preferredcombination are other key players of the autoimmune response which mayact parallel to, dependent on or in concert with TNFα function;especially preferred are IL-18 antagonists including IL-18 antibodies orsoluble IL-18 receptors, or IL-18 binding proteins. It has been shownthat TNFα and IL-18 have overlapping but distinct functions and acombination of antagonists to both may be most effective. Yet anotherpreferred combination are non-depleting anti-CD4 inhibitors. Yet otherpreferred combinations include antagonists of the co-stimulatory pathwayCD80 (B7.1) or CD86 (B7.2) including antibodies, soluble receptors orantagonistic ligands.

Non-limiting examples of therapeutic agents for Psoriatic Arthritis withwhich an antibody, or antibody portion, of the invention can be combinedinclude the following: methotrexate, etanercept, rofecoxib, celecoxib,folic acid, sulfasalazine, naproxen, leflunomide, methylprednisoloneacetate, indomethacin, hydroxychloroquine sulfate, prednisone, sulindac,betamethasone diprop augmented, infliximab, methotrexate, folate,triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam,diclofenac sodium, ketoprofen, meloxicam, methylprednisolone,nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenacsodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodiumthiomalate, hydrocodone bitartrate/apap, ibuprofen, risedronate sodium,sulfadiazine, thioguanine, valdecoxib, alefacept, efalizumab.

IV. Efficacy of TNFα Inhibitor

The invention also provides methods for determining whether a TNFαinhibitor is effective at treating psoriatic arthritis in a subject.Such methods may be used to determine the efficacy of a TNFα inhibitor,including those which are unknown or unconfirmed to have such efficacy.Using the methods described herein, effective TNFα inhibitors may bedetermined or confirmed, and, subsequently, used in the method oftreating psoriatic arthritis.

In one embodiment, the invention provides a method for determining theefficacy of a TNFα inhibitor, including a human TNFα antibody, fortreatment of psoriatic arthritis in a subject, using the AmericanCollege of Rheumatology (ACR) preliminary criteria for improvement inrheumatoid arthritis. ACR criteria measures improvement in tender orswollen joint counts and improvement in three of the following fiveparameters: acute phase reactant (such as sedimentation rate); patientassessment; physician assessment; pain scale; and disability/functionalquestionnaire. ACR criteria is indicated as ACR 20 (a 20 percentimprovement in tender or swollen joint counts as well as 20 percentimprovement in three of the other five criteria), ACR 50 (a 50 percentimprovement in tender or swollen joint counts as well as 50 percentimprovement in three of the other five criteria), and ACR 70 (a 70percent improvement in tender or swollen joint counts as well as 70percent improvement in three of the other five criteria) (see Felson DT, et al. Arthritis Rheum 1995; 38:727-35).

The efficacy of a TNFα inhibitor for treatment of psoriatic arthritis ina patient population who has psoriatic arthritis, may be evaluated bydetermining the percentage of the patient population in whom an ACR20,ACR50 or ACR 70 response has been achieved following administration ofthe TNFα inhibitor.

In one aspect, the invention provides a method of determining theefficacy of a TNFα inhibitor for treating psoriatic arthritis in asubject comprising determining a an ACR20 response of a patientpopulation having psoriatic arthritis and who was administered the TNFαinhibitor, wherein a an ACR20 response in at least about 59% of thepatient population indicates that the TNFα inhibitor is an effectiveTNFα inhibitor for the treatment of psoriatic arthritis in a subject. Inone embodiment, the method further comprises administering the effectiveTNFα inhibitor to a subject to treat psoriatic arthritis. The inventionprovides a method of treatment of psoriatic arthritis in a subjectcomprising administering an effective amount of a TNFα inhibitor to thesubject such that the subject is treated, wherein the effective amountof the TNFα inhibitor was previously identified as achieving an ACR20response in at least about 59% of a patient population having psoriaticarthritis.

In one embodiment, an ACR20 response in at least about 61% of thepatient population indicates that the TNFα inhibitor is an effectiveTNFα inhibitor for the treatment of psoriatic arthritis in a subject. Inone embodiment, an ACR20 response in at least about 65% of the patientpopulation indicates that the TNFα inhibitor is an effective TNFαinhibitor for the treatment of psoriatic arthritis in a subject. In oneembodiment, an ACR20 response in at least about 69% of the patientpopulation indicates that the TNFα inhibitor is an effective TNFαinhibitor for the treatment of psoriatic arthritis in a subject. In oneembodiment, an ACR20 response in at least about 72% of the patientpopulation indicates that the TNFα inhibitor is an effective TNFαinhibitor for the treatment of psoriatic arthritis in a subject. In oneembodiment, an ACR20 response in at least about 75% of the patientpopulation indicates that the TNFα inhibitor is an effective TNFαinhibitor for the treatment of psoriatic arthritis in a subject. Numbersintermediate to the above recited percentages, e.g., 60. 61, 63, 65, 66,70, 72%, as well as all other numbers recited herein, are also intendedto be part of this invention. Ranges of values using a combination ofany of the above recited values as upper and/or lower limits areintended to be included in the scope of the invention. For example, inone embodiment, an ACR20 response in at least about 59% to at leastabout 75% of the patient population indicates that the TNFα inhibitor isan effective TNFα inhibitor for the treatment of psoriatic arthritis ina subject.

In some aspects, the invention provides a method of determining theefficacy of a human TNFα antibody for treating psoriatic arthritis in asubject comprising determining an ACR50 response of a patient populationhaving psoriatic arthritis and who was administered the human TNFαantibody, wherein an ACR50 response in at least about 42% of the patientpopulation indicates that the human TNFα antibody is an effective humanTNFα antibody for the treatment of psoriatic arthritis in a subject. Inone embodiment, the method further comprises administering the effectiveTNFα inhibitor to a subject to treat psoriatic arthritis. The inventionprovides a method of treatment of psoriatic arthritis in a subjectcomprising administering an effective amount of a TNFα inhibitor to thesubject such that the subject is treated, wherein the effective amountof the TNFα inhibitor was previously identified as achieving an ACR50response in at least about 42% of a patient population having psoriaticarthritis.

In one embodiment, an ACR50 response in at least about 49% of thepatient population indicates that the human TNFα antibody is aneffective human TNFα antibody for the treatment of psoriatic arthritisin a subject. In one embodiment, an ACR50 response in at least about 52%of the patient population indicates that the human TNFα antibody is aneffective human TNFα antibody for the treatment of psoriatic arthritisin a subject. In one embodiment, an ACR50 response in at least about 58%of the patient population indicates that the human TNFα antibody is aneffective human TNFα antibody for the treatment of psoriatic arthritisin a subject. In one embodiment, an ACR50 response in at least about 60%of the patient population indicates that the human TNFα antibody is aneffective human TNFα antibody for the treatment of psoriatic arthritisin a subject. Numbers intermediate to the above recited percentages,e.g., 43, 46, 49, 52, 58%, as well as all other numbers recited herein,are also intended to be part of this invention. Ranges of values using acombination of any of the above recited values as upper and/or lowerlimits are intended to be included in the scope of the invention. Forexample, in one embodiment, an ACR50 response in at least about 42% toat least about 60% of the patient population indicates that the humanTNFα antibody is an effective human TNFα antibody for the treatment ofpsoriatic arthritis in a subject.

In some aspects, the invention provides a method of determining theefficacy of a human TNFα antibody for treating psoriatic arthritis in asubject comprising determining an ACR70 response of a patient populationhaving psoriatic arthritis and who was administered the human TNFαantibody, wherein an ACR70 response in at least about 29% of the patientpopulation indicates that the human TNFα antibody is an effective humanTNFα antibody for the treatment of psoriatic arthritis in a subject. Inone embodiment, the method further comprises administering the effectiveTNFα inhibitor to a subject to treat psoriatic arthritis. The inventionprovides a method of treatment of psoriatic arthritis in a subjectcomprising administering an effective amount of a TNFα inhibitor to thesubject such that the subject is treated, wherein the effective amountof the TNFα inhibitor was previously identified as achieving an ACR70response in at least about 29% of a patient population having psoriaticarthritis.

In one embodiment, an ACR70 response in at least about 31% of thepatient population indicates that the human TNFα antibody is aneffective human TNFα antibody for the treatment of psoriatic arthritisin a subject. In one embodiment, an ACR70 response in at least about 35%of the patient population indicates that the human TNFα antibody is aneffective human TNFα antibody for the treatment of psoriatic arthritisin a subject. In one embodiment, an ACR70 response in at least about 37%of the patient population indicates that the human TNFα antibody is aneffective human TNFα antibody for the treatment of psoriatic arthritisin a subject. In one embodiment, an ACR70 response in at least about 40%of the patient population indicates that the human TNFα antibody is aneffective human TNFα antibody for the treatment of psoriatic arthritisin a subject. Numbers intermediate to the above recited percentages,e.g., 30, 31, 32, 37%, as well as all other numbers recited herein, arealso intended to be part of this invention. Ranges of values using acombination of any of the above recited values as upper and/or lowerlimits are intended to be included in the scope of the invention. Forexample, in one embodiment, an ACR70 response in at least about 29% toat least about 40% of the patient population indicates that the humanTNFα antibody is an effective human TNFα antibody for the treatment ofpsoriatic arthritis in a subject.

The invention provides a method for determining the efficacy of a TNFαinhibitor, including a human TNFα antibody, for treatment of psoriaticarthritis in a subject, using the Psoriasis Area and Severity Index(PASI). The PASI is used by dermatologists to assess psoriasis diseaseintensity. This index is based on the quantitative assessment of threetypical signs of psoriatic lesions: erythema, infiltration, anddesquamation, combined with the skin surface area involvement (seeFredriksson T, et al. Dermatologica 1978; 157: 238-41). PASI isindicated as PASI50 (a 50 percent improvement in PASI from baseline),PASI75 (a 75 percent improvement in PASI from baseline), PASI90 (a 90percent improvement in PASI from baseline), and PASI100 (a 100 percentimprovement in PASI from baseline).

The efficacy of a TNFα inhibitor for treatment of psoriatic arthritis ina patient population who has psoriatic arthritis, may be evaluated bydetermining the percentage of the patient population in whom a PASI50,PASI75, PASI90, or PASI100 response has been achieved followingadministration of the TNFα inhibitor.

In some aspects, the invention provides a method of determining theefficacy of a TNFα inhibitor for treating psoriatic arthritis in asubject comprising determining a PASI50 response of a patient populationhaving psoriatic arthritis and who was administered the TNFα inhibitor,wherein a PASI50 response in at least about 55% of the patientpopulation indicates that the TNFα inhibitor is an effective TNFαinhibitor for the treatment of psoriatic arthritis in a subject. In oneembodiment, the method further comprises administering the effectiveTNFα inhibitor to a subject to treat psoriatic arthritis. In someaspects, the present invention provides a method of treating psoriaticarthritis in a subject comprising administering an effective TNFαinhibitor to the subject such that psoriatic arthritis is treated,wherein the effective TNFα inhibitor was previously identified asachieving a PASI50 response in at least about 55% of the patientpopulation.

In one embodiment, a PASI50 response in at least about 60% of thepatient population indicates that the TNFα inhibitor is an effectiveTNFα inhibitor for the treatment of psoriatic arthritis in a subject. Inone embodiment, a PASI50 response in at least about 65% of the patientpopulation indicates that the TNFα inhibitor is an effective TNFαinhibitor for the treatment of psoriatic arthritis in a subject. In oneembodiment, a PASI50 response in at least about 70% of the patientpopulation indicates that the TNFα inhibitor is an effective TNFαinhibitor for the treatment of psoriatic arthritis in a subject. In oneembodiment, a PASI50 response in at least about 75% of the patientpopulation indicates that the TNFα inhibitor is an effective TNFαinhibitor for the treatment of psoriatic arthritis in a subject. In oneembodiment, a PASI50 response in at least about 80% of the patientpopulation indicates that the TNFα inhibitor is an effective TNFαinhibitor for the treatment of psoriatic arthritis in a subject. Numbersintermediate to the above recited percentages, e.g., 69, 71%, as well asall other numbers recited herein, are also intended to be part of thisinvention. Ranges of values using a combination of any of the aboverecited values as upper and/or lower limits are intended to be includedin the scope of the invention. For example, in one embodiment, a PASI50response in at least about 55% to at least about 80% of the patientpopulation indicates that the TNFα inhibitor is an effective TNFαinhibitor for the treatment of psoriatic arthritis in a subject.

In some aspects, the invention provides a method of determining theefficacy of a human TNFα antibody for treating psoriatic arthritis in asubject comprising determining a PASI75 response of a patient populationhaving psoriatic arthritis and who was administered the human TNFαantibody, wherein a PASI75 response in at least about 65% of the patientpopulation indicates that the human TNFα antibody is an effective humanTNFα antibody for the treatment of psoriatic arthritis in a subject. INone embodiment, the method further comprises administering the effectivehuman TNFα antibody to a subject to treat psoriatic arthritis. In someaspects, a method of treating psoriatic arthritis in a subjectcomprising administering an effective human TNFα antibody to the subjectsuch that psoriatic arthritis is treated, wherein the effective humanTNFα antibody was previously identified as achieving a PASI75 responsein at least about 65% of the patient population.

In one embodiment, a PASI75 response in at least about 70% of thepatient population indicates that the human TNFα antibody is aneffective human TNFα antibody for the treatment of psoriatic arthritisin a subject. In one embodiment, a PASI75 response in at least about 75%of the patient population indicates that the human TNFα antibody is aneffective human TNFα antibody for the treatment of psoriatic arthritisin a subject. Numbers intermediate to the above recited percentages,e.g., 69, 71%, as well as all other numbers recited herein, are alsointended to be part of this invention. Ranges of values using acombination of any of the above recited values as upper and/or lowerlimits are intended to be included in the scope of the invention. Forexample, in one embodiment, a PASI75 response in at least about 65% toat least about 75% of the patient population indicates that the humanTNFα antibody is an effective human TNFα antibody for the treatment ofpsoriatic arthritis in a subject.

In some aspects, the invention provides a method of determining theefficacy of a TNFα inhibitor for treating psoriatic arthritis in asubject comprising determining a PASI90 response of a patient populationhaving psoriatic arthritis and who was administered the TNFα inhibitor,wherein a PASI90 response in at least about 43% of the patientpopulation indicates that the TNFα inhibitor is an effective TNFαinhibitor for the treatment of psoriatic arthritis in a subject. In oneembodiment, the invention further comprises administering the effectiveTNFα inhibitor to a subject to treat psoriatic arthritis. In someaspects, the invention provides a method of treating psoriatic arthritisin a subject comprising administering an effective TNFα inhibitor to thesubject such that psoriatic arthritis is treated, wherein the effectiveTNFα inhibitor was previously identified as achieving a PASI90 responsein at least about 43% of the patient population.

In one embodiment, a PASI90 response in at least about 50% of thepatient population indicates that the TNFα inhibitor is an effectiveTNFα inhibitor for the treatment of psoriatic arthritis in a subject. Inone embodiment, a PASI90 response in at least about 55% of the patientpopulation indicates that the TNFα inhibitor is an effective TNFαinhibitor for the treatment of psoriatic arthritis in a subject. In oneembodiment, a PASI90 response in at least about 60% of the patientpopulation indicates that the TNFα inhibitor is an effective TNFαinhibitor for the treatment of psoriatic arthritis in a subject. In oneembodiment, a PASI90 response in at least about 65% of the patientpopulation indicates that the TNFα inhibitor is an effective TNFαinhibitor for the treatment of psoriatic arthritis in a subject. In oneembodiment, a PASI90 response in at least about 70% of the patientpopulation indicates that the TNFα inhibitor is an effective TNFαinhibitor for the treatment of psoriatic arthritis in a subject. In oneembodiment, a PASI90 response in at least about 75% of the patientpopulation indicates that the TNFα inhibitor is an effective TNFαinhibitor for the treatment of psoriatic arthritis in a subject. Numbersintermediate to the above recited percentages, e.g., 71%, as well as allother numbers recited herein, are also intended to be part of thisinvention. Ranges of values using a combination of any of the aboverecited values as upper and/or lower limits are intended to be includedin the scope of the invention. For example, in one embodiment, a PASI90response in at least about 43% to at least about 75% of the patientpopulation indicates that the TNFα inhibitor is an effective TNFαinhibitor for the treatment of psoriatic arthritis in a subject

In some aspects, the invention provides a method of determining theefficacy of a TNFα inhibitor for treating psoriatic arthritis in asubject comprising determining a PASI100 response of a patientpopulation having psoriatic arthritis and who was administered the TNFαinhibitor, wherein a PASI100 response in at least about 10% of thepatient population indicates that the TNFα inhibitor is an effectiveTNFα inhibitor for the treatment of psoriatic arthritis in a subject. Inone embodiment, the invention further comprises administering theeffective TNFα inhibitor to a subject to treat psoriatic arthritis. Insome aspects, the invention provides a method of treating psoriaticarthritis in a subject comprising administering an effective TNFαinhibitor to the subject such that psoriatic arthritis is treated,wherein the effective TNFα inhibitor was previously identified asachieving a PASI100 response in at least about 10% of the patientpopulation.

In one embodiment, a PASI100 response in at least about 20% of thepatient population indicates that the TNFα inhibitor is an effectiveTNFα inhibitor for the treatment of psoriatic arthritis in a subject. Inone embodiment, a PASI100 response in at least about 30% of the patientpopulation indicates that the TNFα inhibitor is an effective TNFαinhibitor for the treatment of psoriatic arthritis in a subject. In oneembodiment, a PASI100 response in at least about 40% of the patientpopulation indicates that the TNFα inhibitor is an effective TNFαinhibitor for the treatment of psoriatic arthritis in a subject. In oneembodiment, a PASI100 response in at least about 45% of the patientpopulation indicates that the TNFα inhibitor is an effective TNFαinhibitor for the treatment of psoriatic arthritis in a subject. Numbersintermediate to the above recited percentages, e.g., 32, 43%, as well asall other numbers recited herein, are also intended to be part of thisinvention. Ranges of values using a combination of any of the aboverecited values as upper and/or lower limits are intended to be includedin the scope of the invention. For example, in one embodiment a PASI100response in at least about 10% to at least about 45% of the patientpopulation indicates that the TNFα inhibitor is an effective TNFαinhibitor for the treatment of psoriatic arthritis in a subject

The invention provides a method for determining the efficacy of a TNFαinhibitor, including a human TNFα antibody, for treatment of psoriaticarthritis in a subject, using the Physician's Global Assessment scale(PGA). PGA is used to assess psoriasis activity and follow clinicalresponse to treatment. It is a score that summarizes the overall quality(erythema, scaling and thickness) and extent of plaques relative to thebaseline assessment. A patient's response is rated as worse, poor(0-24%), fair (25-49%), good (50-74%), excellent (75-99%), or cleared(100%) (see van der Kerkhof P. Br J Dermatol 1997; 137:661-662).

The efficacy of a TNFα inhibitor for treatment of psoriatic arthritis ina patient population who has psoriatic arthritis, can be evaluated bydetermining the percentage of the patient population in whom a PGA of“Clear” or “Almost Clear” has been achieved following administration ofthe TNFα inhibitor, including a human TNFα antibody.

In some aspects, the invention provides a method of determining theefficacy of a human TNFα antibody for treating psoriatic arthritis in asubject comprising determining a PGA response of “Clear” or “AlmostClear,” of a patient population having psoriatic arthritis and who wasadministered the human TNFα antibody, wherein a PGA response of “Clear”or “Almost Clear,” in at least about 30% of the patient populationindicates that the human TNFα antibody is an effective human TNFαantibody for the treatment of psoriatic arthritis in a subject. In oneembodiment, the invention further comprises administering the effectivehuman TNFα antibody to a subject to treat psoriatic arthritis. In someaspects, the invention provides a method of treating psoriatic arthritisin a subject comprising administering an effective human TNFα antibodyto the subject such that psoriatic arthritis is treated, wherein theeffective human TNFα antibody was previously identified as achieving aPGA response of “Clear” or “Almost Clear,” in at least about 30% of thepatient population.

In one embodiment, a PGA response of “Clear” or “Almost Clear,” in atleast about 45% of the patient population indicates that the human TNFαantibody is an effective human TNFα antibody for the treatment ofpsoriatic arthritis in a subject. In one embodiment, a PGA response of“Clear” or “Almost Clear,” in at least about 60% of the patientpopulation indicates that the human TNFα antibody is an effective humanTNFα antibody for the treatment of psoriatic arthritis in a subject. Inone embodiment, a PGA response of “Clear” or “Almost Clear,” in at leastabout 75% of the patient population indicates that the human TNFαantibody is an effective human TNFα antibody for the treatment ofpsoriatic arthritis in a subject. In one embodiment, a PGA response of“Clear” or “Almost Clear,” in at least about 80% of the patientpopulation indicates that the human TNFα antibody is an effective humanTNFα antibody for the treatment of psoriatic arthritis in a subject.Numbers intermediate to the above recited percentages, e.g., 32, 38,76%, as well as all other numbers recited herein, are also intended tobe part of this invention. Ranges of values using a combination of anyof the above recited values as upper and/or lower limits are intended tobe included in the scope of the invention. For example, in oneembodiment a PGA response of “Clear” or “Almost Clear,” in at leastabout 30% to at least about 80% of the patient population indicates thatthe human TNFα antibody is an effective human TNFα antibody for thetreatment of psoriatic arthritis in a subject.

Additional measures can be used to evaluate the efficacy of a TNFαinhibitor for treatment of psoriatic arthritis, or improvement in thequality of life (QOL) and physical function in a patient population whohas psoriatic arthritis, following administration of the TNFα inhibitor,including a human TNFα antibody, or antigen binding fragment thereof.Examples of QOL measures include the Short-Form 36 (SF-36),^([78)] abroad measure of physical and mental domains which has been used andvalidated in many diseases, and the Dermatology Life Quality Index(DLQI). For example, in one embodiment, a Health Assessment Questionaire(HAQ) is used to evaluate the efficacy of a TNFα inhibitor for treatmentof psoriatic arthritis in a patient population who has psoriaticarthritis. The HAQ is a standardized disability questionnaire that wasinitially developed for use in rheumatoid arthritis. The HAQ-DI assessesthe difficulty a patient has accomplishing tasks in eight functionalareas (dressing, arising, eating, walking, hygiene, reaching, grippingand other activities of daily living). A high HAQ score has been shownto be a strong predictor of morbidity and mortality in RA, and low HAQscores are predictive of better outcomes (see Fries J F, et al.Arthritis Rheum 1980; 23:137-45).

A number of measures of fatigue have been developed as well. Fatigue isan important domain to PsA patients; even in patients without evidentclinical psoriasis, fatigue is often overlooked by assessors, yet iscapable of significant improvement with newer therapies. In oneembodiment, the Functional Assessment of Chronic Illness Therapy (FACIT)can be used to evaluate the efficacy of a TNFα inhibitor for thetreatment of psoriatic arthritis in a patient population who haspsoriatic arthritis.

It should be noted that the Examples provided herein represent differentmethods of determining the efficacy of a TNFα inhibitor, such as a humanTNFα antibody, or antigen-binding portion thereof. As such, data andresults described in the Examples section which shows efficacy of a TNFαinhibitor, e.g., treatment of psoriatic arthritis, are included in themethods of determining efficacy of the invention.

Time points for determining efficacy will be understood by those ofskill in the art to depend on the type of efficacy being determined,e.g., treatment of early psoriatic arthritis, treatment of establishedpsoriatic arthritis. In one embodiment, measurements in scores, e.g.,ACR20/50/70 response, or PASI50/75/90 response, may be measured againsta subject's baseline score. Generally, a baseline refers to ameasurement or score of a patient before treatment, i.e. week 0. Othertime points may also be included as a starting point in determiningefficacy, however.

Patient populations described in the methods of the invention aregenerally selected based on common characteristics, such as, but notlimited to, subjects diagnosed with psoriatic arthritis. Such a patientpopulation would be appropriate for determining the efficacy of the TNFαinhibitor for treating psoriatic arthritis in the given patientpopulation. In one embodiment, the patient population is an adultpopulation, e.g, older than 17 years of age or older than 18 years ofage.

In one embodiment, the methods of the invention for determining whethera TNFα inhibitor is an effective TNFα inhibitor, include determiningchanges, improvements, measurements, etc., in psoriatic arthritis usingappropriate indices known in the art, e.g., ACR, PASI, PGA, HAQ, DLQI.from a patient population who has already been administered the TNFαinhibitor. Such a patient population may be pre-selected according tocommon characteristics, .e.g., psoriatic arthritis, loss of response toDMARDs, and may have already been given the TNFα inhibitor.Administration of the TNFα inhibitor may or may not be performed by thesame person of ordinary skill who is determining the efficacy of theTNFα inhibitor in accordance with the teachings of the specification.

In one embodiment, the methods of the invention comprise administeringthe TNFα inhibitor to the subjects of a patient population anddetermining the efficacy of the TNFα inhibitor by determining changes,improvements, measurements, etc., using psoriatic arthritis indicesknown in the art, in the patient population in comparison to theExamples set forth below. For example, in one embodiment the inventionincludes a method for determining the efficacy of a TNFα inhibitor forthe treatment of psoriatic arthritis comprising administering the TNFαinhibitor to a preselected patient population having psoriaticarthritis; and determining the effectiveness of the TNFα inhibitor byusing a mean baseline ACR score of the patient population and a meanACR20 score following administration of the TNFα inhibitor, wherein aACR20 achieved in at least about 59% of the patient population indicatesthat the TNFα inhibitor is effective for the treatment of psoriaticarthritis.

Methods of the invention relating to determining efficacy, i.e.,determining whether a TNFα inhibitor is an effective TNFα inhibitor, mayalso be applied to specific patient populations within the overallpatient population who together have specific, common characteristics,i.e., a subpopulation. For example, the patient population may comprisepatients on who previously failed DMARD therapy. In another example, thepatient population may comprise patients who did not previously failDMARD therapy.

In addition, while the above methods are described in terms of patientpopulations, methods of efficacy described herein may also be applied toindividual subjects. For example, a method for determining efficacy maycomprise determining whether a subject who has psoriatic arthritis, andwho is on a dosage regimen comprising a human TNFα antibody, is able tomaintain an ACR20 response.

The Examples and discoveries described herein are representative of aTNFα inhibitor, i.e., adalimumab, which is effective for treatingpsoriatic arthritis. As such, the studies and results described in theExamples section herein may be used as a guideline for determining theefficacy of a TNFα inhibitor, i.e., whether a TNFα inhibitor is aneffective TNFα inhibitor for the treatment of psoriatic arthritis. Inone embodiment, methods of determining efficacy described herein may beused to determine whether a TNFα inhibitor is bioequivalent to anotherTNFα inhibitor.

In one embodiment, the article of manufacture of the invention comprisesinstructions regarding how to determine the efficacy of the TNFinhibitor for the treatment of psoriatic arthritis.

The present invention is further illustrated by the following exampleswhich should not be construed as limiting in any way. Examples 1 to 12refer to Study G. The baseline demographic and clinical characteristicsfor patients participating in Study G are provided in Table 1.

TABLE 1 Baseline Demographics and Disease Characteristics PlaceboAdalimumab Every Other 40 mg Every Other Week Week (EOW) (EOW)Characteristic N = 162 N = 151 Age (years) 49.2 ± 11.1 48.6 ± 12.5 %Male 54.9 56.3 % Caucasian 93.8 97.4 Body Weight (kg) 85.5 ± 16.5 86.0 ±20.6 Rheumatoid Factor 90.1 89.4 negative (%) Duration of Psoriatic 9.2± 8.7 9.8 ± 8.3 Arthritis (years) Duration of Psoriasis 17.1 ± 12.6 17.2± 12.0 (years) No. of previous DMARDs 1.5 ± 1.2 1.5 ± 1.2 % MTX use 50.051.0 *Mean values ± standard deviations, except percentages.

The study design for Study G was as follows. 313 patients wererandomized during a screening period. At week 0, patients were splitinto two groups: the first group included 151 patients who received 40mg every other week of Adalimumab; and the second group included 162patients who received placebo every other week. The study was conductedin a double blind manner for 24 weeks. Statistical analysis wasconducted at week 24.

Patients were exclude for prior anti-TNF therapy; Alefacept within 12weeks prior to study entry; other biologics within 6 weeks prior tostudy entry; DMARDs (except MTX) within 4 weeks prior to study entry;systemic therapies for psoriasis within 4 weeks prior to study entry;and phototherapy and topicals within 2 weeks prior to study entry.

Example 1: Adalimumab is Efficacious in Treating Skin Disease inPsoriatic Arthritis: Subanalysis of Moderate Vs. Severe Psoriasis

A study was performed to evaluate whether the efficacy of adalimumab forcutaneous disease in patients with psoriatic arthritis (PsA) varies withseverity of psoriasis. Prior to this study, it was unknown whether theresponse of psoriasis to adalimumab therapy in previous, related studieswas affected by the level of skin disease at baseline.

A randomized Phase III study of adalimumab was studied in patients withactive PsA (≧3 swollen and ≧3 tender joints) who had failed NSAIDtherapy (see above description of Study G). Randomization was centrallystratified by methotrexate (MTX) use and extent of psoriasis (<3% or ≧3%body surface area [BSA]) at baseline. Patients completing Week 24 wereeligible to continue in an open-label extension study.

Patients were included if they had a history of psoriasis; were over 18years; ≧3 swollen and ≧3 tender joints; and inadequate response to NSAIDtherapy. Exclusion criteria included prior anti-TNF therapy; alefaceptwithin 12 weeks prior to study entry; other biologics within 6 weeksprior to study entry; DMARDs (except MTX) within 4 weeks prior to studyentry; systemic therapies for psoriasis within 4 weeks prior to studyentry; and phototherapy and topicals within 2 weeks prior to studyentry.

Patients were stratified by methotrexate use (yes/no) and degree ofpsoriasis (<3% and ≧3% BSA involvement) and received adalimumab 40 mgevery other week or placebo for 24 weeks.

Efficacy measures included: ACR response criteria (co-primary endpoint:ACR20 response at Week 12); Psoriasis Area and Severity Index (PAST) inpatients with significant psoriasis at study entry (≧3% BSA); andPhysician's Global Assessment (PGA) of psoriasis. This study examinedpatients according to the severity of psoriasis at baseline: PASI <10vs. PASI10

Thus, efficacy measures in patients with psoriasis affecting ≧3% BSA atbaseline included PASI, PGA of psoriasis, and DLQI. ACR responsecriteria was also used as an efficacy measurement. A post-hoc analysiswas conducted for patients with baseline PASI <10 vs. those with PASI≧10. PASI analyses were by NRI, and PGA and DLQI scores were calculatedas LOCF. Table 2 shows the baseline psoriasis scores ofadalimumab-treated patients grouped by psoriatic severity.

TABLE 2 Baseline psoriasis scores of adalimumab-treated patients groupedby psoriatic severity. PASI <10 PASI ≧10 Characteristics* N = 53 N = 16Mean PASI ± SD (0-72) 4.8 ± 2.4 16.1 ± 6.4 PGA “Clear” or “Almost Clear”1 (1.9%) 0 (0%) Mean DLQI ± SD* 6.6 ± 4.8 15.4 ± 7.8 *N values for meanDLQI at baseline are 51 (PASI <10) and 14 (PASI ≧10).

Baseline data was similar between the groups. ACR responses weresignificantly better with adalimumab than placebo, as ACR20/50/70responses at Week 24 were 57*/39*/23* for adalimumab vs. 15/6/1 forplacebo (*p≦0.001, placebo vs. adalimumab).

PASI responses were evaluated for 138 of 313 enrolled patients. Baselinedata for this subset were also well-matched, with baseline PASI scoresof 7.4±6.1 for adalimumab and 8.3±7.3 for placebo.

PASI responses had rapid onset and were maintained out to Week 24, whenapproximately half of adalimumab patients had achieved a PASI 90response. The trend in mean percent improvement in PASI scores over 24weeks is described in FIG. 1. Overall, PASI 50/75/90 responses at Week24 were 75*/59*/42* for adalimumab (n=69) vs. 12/1/0 for placebo (n=69)(*p<0.001 adalimumab vs. placebo, PASI 50/75/90 by non-responderimputation).

PASI responses at week 24 were examined in accordance with diseaseseverity. Of the 69 patients on adalimumab who were evaluated for PASIresponse, 53 had mild to moderate psoriasis (baseline PASI <10), and 16had moderate to severe psoriasis (baseline PASI ≧10). Mean baseline PASIscores for patients with mild psoriasis vs. patients with moderate tosevere psoriasis were 4.8±2.4 vs. 16.1±6.4. At week 24, the twosubgroups of adalimumab-treated patients (PASI <10 and PASI ≧10) hadsimilar and clinically significant PASI 50, 70, and 90 response rates.After 24 weeks, the % of patients who had achieved PASI50/75/90 responserates were similar: 74*/62*/43* for those with PASI <10 (n=53) and81*/50*/38† for those with PASI ≧10 (n=16) (* P≦0.001; †=0.005, for adavs. placebo, non-responder imputation).

The distribution of PGA scores improved from baseline with 24 weeks ofadalimumab treatment in both disease severity groups (PASI <10 and PASI≧10), as shown below in Table 3.

TABLE 3 PGA at Baseline and Week 24 by Disease Severity Including PASI≧10 % Patients with PASI ≧10 Baseline Week 24 Severe 12.5 0 Moderate toSevere 50 6.3 Moderate 25 25 Mild to Moderate 12.5 12.5 Mild 0 18.8Almost Clear 0 18.8 Clear 0 18.8

The percentage of patients with a PGA of “Clear” or “Almost Clear” at 24weeks was 76% for those with PASI <10 and 38% for those with PASI ≧10,as shown in Table 4.

TABLE 4 Percentage of Patients with PGA of “Almost Clear” or “Clear”PASI <10 PASI ≧10 Placebo Adalimumab Adalimumab (n = 50) (n = 53)Placebo (n = 19) (n = 16) % of Patients 14 76* 0 38† with PGA of “Clear”or “Almost Clear” *P < 0.001, †P < 0.01 adalimumab vs. placebo (placebodata not shown)

For patients with moderate psoriasis, the PGA appeared to correlate withPASI 50-75 responses; for patients with severe psoriasis, thecorrelation was with PASI 90.

At week 24, both subgroups of adalimumab-treated patients (PASI <10 andPASI ≧0.10) achieved meaningful improvements in quality of life asmeasure by DLQI. Mean change in DLQI at 24 weeks for patients whoreceived Adalimumab with PASI <10 was −4.6, and for patients whoreceived Adalimumab with PASI ≧10 it was −10.6. Mean change in DLQI at24 weeks for patients who received placebo with PASI <10 was −0.6, and-0.9 for patients who received placebo with PASI ≧10. Quality of lifeimprovements were greater for patients with severe psoriasis. Adalimumabwas generally well-tolerated during the trial, as previously reported.

Rates of individual adverse events (AE) and serious adverse events (SAE)were comparable between adalimumab and placebo, as shown below in Table5.

TABLE 5 Common adverse events >5% at week 24 Placebo Adalimumab eow 40mg eow N = 162 N = 151 n (%) n (%) Any AE 130 (80.2) 122 (80.8)  Any SAE 7 (4.3) 5 (3.3) Upper Respiratory Tract Infection  24 (14.8) 19 (12.6)NOS Nasopharyngitis 15 (9.3) 15 (9.9)  Injection site reaction NOS  5(3.1) 10 (6.6)  Headache 14 (8.6) 9 (6.0) Hypertension NOS  5 (3.1) 8(5.3) PsA aggravated 11 (6.8) 5 (3.3) Psoriasis aggravated 10 (6.2) 3(2.0) Arthralgia  9 (5.6) 3 (2.0) Diarrhea NOS  9 (5.6) 3 (2.0)

In conclusion, adalimumab is efficacious for skin and joint disease inpatients with PsA. In this post-hoc analysis, clinically significantimprovements were observed for patients with moderate to severepsoriasis, as well as those with mild to moderate psoriasis. Thus, thebaseline severity of skin disease did not affect the efficacy ofadalimumab in the treatment of psoriasis.

Example 2: Correlation of Skin and Joint Responses in PsoriaticArthritis

Previous studies have shown that anti-TNF therapy with adalimumab (ada)is efficacious against the arthritis and skin disease of psoriaticarthritis (PsA) for up to 24 weeks (wks). Patients (pts) completingStudy G were eligible to enroll in an open-label extension (OLE) trial.The objective of this study was to evaluate the frequency of concurrentjoint and skin responses in PsA patients treated with ada for up to 48wks in Study G (described above).

Patients completing the 24-week trial were eligible to enroll in an OLEstudy to receive ada 40 mg eow. Skin responses were evaluated only inpatients with psoriasis affecting ≧3% BSA at baseline. For the presentpost-hoc subanalysis, these patients were categorized according to theresponse to treatment of psoriasis (PASI nonresponse, 50, 75, 90) and ofarthritis (ACR nonresponse, 20, 50, 70) at Wks 24 and 48, compared tobaseline. ACR and PASI scores were analyzed in the intent-to-treatpopulation, using nonresponder imputation for missing data.

Baseline demographics/disease characteristics were similar betweenrandomizaton groups (162 placebo, 151 ada). For patients with baselinepsoriasis affecting ≧3% BSA (69 placebo, 69 ada), mean baseline PASIscores were 8.3 and 7.4. In these 138 patients, at Wk 24 the responserates for ACR20/50/70 were 14/6/0 (placebo) and 54/36/23 (ada), and forPASI 50/75/90 were 12/1/0 (placebo) and 75/59/42 (ada). Among the 69patients in the ada arm, an ACR20 and/or PASI75 response was achieved by75% at Wk 24 and by 68% at Wk 48. Simultaneous ACR20 and PASI70responses were achieved by 38% and 45% at Wks 24 and 48, andsimultaneous ACR70 and PASI75 responses were achieved by 22% and 26% atWks 24 and 48, respectively. Among ada patients who achieved an ACR50 oran ACR70 response, a PASI75 response was achieved at Wk 24 by 84% and94%, respectively, and at Wk 48 by 83% and 95% (Table 6).

TABLE 6 PASI responses among patients with an ACR20, 50, or 70 responseWeek 24 Week 48 ACR20 ACR50 ACR70 ACR20 ACR50 ACR70 n = 37 n = 25 N = 16n = 38 n = 29 n = 19 PASI50 % 86 92 94 87 90 100 PASI75 % 70 84 94 82 8395 PASI90 % 54 64 69 61 62 63 *Numbers of ada-treated patients, of 69total, with the indicated level of ACR response at Wks 24 or 48,compared with baseline; PASI responses are % of the above n values.Furthermore, among ACR non-responders (<ACR20), a PASI75 or PASI90response was achieved at Wk 24 by 47% and 28%, respectively, and at Wk48 by 29% and 29%.

As shown in Table 7 (below), 30% of evaluated patients (n=69) achievedconcurrent ACR50 and PASI 75 responses. In addition, 16% of patientsachieved concurrent ACR70 and PASI 90 responses.

TABLE 7 Concurrent Skin-Joint Responses at Week 24 PASI 75 PASI 90 %patients with 38 29 ACR20 % patients with 30 23 ACR50 % patients with 2216 ACR70

At week 24, 47% of patients with <ACR20 response, i.e., ACRnon-responders, achieved a PASI 75 response, and 70% of ACR20 respondersachieved a PASI 75 response. Furthermore, 84% of ACR50 responders and94% of ACR70 responders achieved a PASI 75 response. ACR response rateswere higher for patients who achieved a ≧PASI 75 response than those whodid not (see Table 8).

TABLE 8 ACR Response Rates for PASI75 Responders at Week 24 PASI <75PASI ≧75 % patients with 39 63 ACR20 % patients with 14 51 ACR50 %patients with 4 37 ACR70

In conclusion, adalimumab was simultaneously efficacious against theskin disease and joint inflammation of patients with PsA. SimultaneousACR70 and PASI75 responses occurred in 26% of ada-treated patients.PASI75 responses were frequent among ada-treated ACR non-responders(<ACR20) and as the level of joint response increased, the frequency ofPASI 75 skin response also increased, reaching 95% in ACR70 responders.Concurrent high-level skin and joint responses were frequent, with 30%of patients achieving both a PASI 75 and an ACR50 response. Finally, asthe level of one type of response (skin or joint) increased, so did thefrequency of the other, with 94% of ACR70 responders also having a PASI75 response.

Example 3: Adalimumab is Efficacious in Treating Skin Disease inPsoriatic Arthritis: Subanalysis by Severity of Psoriasis

Results from Study G demonstrated that adalimumab (ada) is an effectivetreatment for the joint and skin disease of psoriatic arthritis (PsA)for up to 24 wks. Patients (pts) completing Study G were eligible toenroll in an open label extension (OLE) trial. The relationship betweenthe severity of skin disease in Study G patients, and the efficacy ofada as treatment for PsA skin disease, is described in the instantexample.

This study was conducted to determine the 48-week efficacy of ada forPsA skin disease in patients with mild-to-moderate versusmoderate-to-severe psoriasis (Ps) at baseline (BL). The present post-hocanalysis examined subgroups of patients enrolled in Study G (see abovefor description of study characteristics) with mild-to-moderate Ps (PASI<10) vs. moderate-to-severe Ps (PASI ≧10) at BL. Analyses were conductedon the ITT population, using NRI for the PASI response rates and LOCFfor the Psoriasis Area and Severity Index (PAST), Physician's GlobalAssessment (PGA) and Dermatology Life Quality Index (DLQI).

A total of 313 patients (151 ada, 162 pbo) enrolled in Study G and 285entered the OLE. BL data were similar between randomization groups. PASIresponses were evaluated for 138 patients (69 ada, 69 pbo), in whom BLdata were well matched, and the BL PASI scores were 7.4±6.1 for ada and8.3±7.3 for pbo. Overall, PASI 50/75/90 responses at Week 24 were75/59/42 for ada versus 12/1/0 for pbo, and at Week 48 were 70/58/46 forpatients from the ada randomization arm. Among the 69 ada patients inwhom skin efficacy was evaluated, the BL PASI was <10 in 53 patients(mean PASI, 4.8±2.4) and was ≧10 in 16 patients (mean PASI, 16.1±6.4).At Weeks 24 and 48, the mean PASI score and the DLQI both showed largerimprovement in the PASI group (Table 9), whereas this difference was notseen in the PASI50/75/90 responses (PASI <10: 74/62/43 Wk 24 and72/66/51 Wk 48; PASI ≧10: 81/50/38 and 63/31/31; p>0.05, for allcomparisons). Consistent with their milder skin disease at BL, the PASI<10 group had better PGA results than the PASI ≧10 group (see Table 9).These Week 24 PASI, DLQI and PGA results were all significantly betterthan observed in the corresponding pbo patients (p≦0.001 for PASI <10;p≦0.005 for PASI ≧10).

TABLE 9 Psoriasis-related changes following ada in Study G patients bybaseline Ps severity. PASI PASI90 DLQI PGA PASI < 10 PASI ≧ 10 PASI < 10PASI ≧10 PASI < 10 PASI ≧ 10 PASI < 10 PASI ≧ 10 n = 53 n = 16 n = 53 n= 16 n = 51 n = 14 n = 53 N = 16 Baseline 4.8 16.1 6.6 15.4 2 0 Wk 24*−3.6 −10.7 43 38 −4.6 −10.6 76 38 Wk 48* −3.8 −10.0 51 31 −4.1 −8.1 7231 *Mean change from baseline for PASI, DLQI, % for PASI90 and PGA clearor almost clear.Ada generally had a good safety profile and was well-tolerated duringthe blinded phase of Study G and the first 24 weeks of the OLE trial.

In conclusion, clinically meaningful improvements were observed forpatients with moderate-to-severe Ps, as well as those withmild-to-moderate Ps in this post-hoc analysis of PsA patients treatedfor 48 weeks.

Example 4: Adalimumab Efficacy in Psoriatic Arthritis Patients withOligoarticular Arthritis

Initial studies from Study G have shown that anti-TNF treatment withadalimumab (ada) is efficacious for arthritis and skin disease ofpsoriatic arthritis (PsA) for up to 24 weeks. Patients (pts) completingStudy G could enroll in an open-label extension (OLE) trial. Mostpatients in Study G had polyarticular arthritis. The effect of ada onthe subset of PsA patients with oligoarticular arthritis, as originallydefined by Moll and Wright (Wright and Moll. Psoriatic arthritis.Seronegative polyarthritis. Amsterdam: North Holland Publishing Co,1976:169-223) was not known prior to this study. Thus, the purpose ofthis study was to determine the efficacy of ada for arthritis andphysical function of PsA patients with oligoarthritis in Study G.

Study G is described above. The present post-hoc analysis examinedsubgroups of patients who had oligoarthritis at baseline (BL), definedas a tender joint count (TJC) <5 or a swollen joint count (SJC) <5.Analyses were conducted on the intention to treat population (ITTpopulation), using nonresponder imputation for the ACR response ratesand last observation carried forward for the HAQ-DI scores.

A total of 313 patients (151 ada, 162 pbo) enrolled in Study G and 285entered the OLE. BL data were similar between randomization groups.ACR20/50/70 responses and the mean change in HAQ scores at Week 24 were57/39/23 and −0.4, respectively, for ada patients vs. 15/6/1 and −0.1for pbo patients, and at Week 48 were 61/46/31 and −0.4 for patientsfrom the ada randomization arm. At Week 24, the ACR responses and meanchange in HAQ scores of ada-treated patients with BL TJC <5 or SJC <5were comparable to those of the overall ada cohort in Study G (Table10). In ada-treated patients with SJC <5, the Week 24 ACR responses(p<0.05) and mean change in HAQ scores (p<0.01) were superior to thoseof patients treated with pbo (Table 10). ACR responses and mean changein HAQ scores in ada-treated patients with TJC <5 or SJC <5 weremaintained at Week 48 (Table 10).

TABLE 10 Clinical responses in PsA patients with Oligoarthritis in StudyG TJC <5 SJC <5 Ada Pbo Ada Pbo n = 10 n = 5 n = 24 n = 17 ACR20/50/70Wk 24 60/20/0 20/0/0 58*/42/*29* 18/6/0 ACR20/50/70 Wk 48 50/40/20 N/A63/54/50 N/A HAQ baseline 0.6 0.6 0.9 1.0 Mean Δ HAQ Wk 24 −0.3 0 −0.5**0 Mean Δ HAQ Wk 48 −0.2 N/A −0.5 N/A *p < 0.05, **p < 0.01 ada vs.placebo; N/A., not available because pbo patients received ada afterWeek 24; Week 48 results are for ada randomization arm patients only vs.baseline. p values not determined for Week 48.

In conclusion, while the numbers of patients with oligoarthritis issmall, the results indicate improvements in arthritis and physicalfunction that are comparable to those of the overall PsA trialpopulation. Thus, adalimumab was effective at treating this specificsubpopulation of PsA patients.

Example 5: Adalimumab is Efficacious in Treating Joint Disease in Earlyand Established Psoriatic Arthritis

Patients (pts) completing Study G were eligible to enroll in an openlabel extension (OLE) trial. The objective of this study was todetermine the 24- and 48-week efficacy of adalimumab (ada) for arthritisand disability in Study G patients classified according to diseaseduration at baseline (BL).

Study G is described above. Upon completion of Study G, ada and placebo(pbo) patients were eligible to receive ada 40 mg every other week (eow)in the OLE trial; a dosage increase to 40 mg weekly was allowed on orafter Week 36 for patients with <20% improvement in TJC and <20%improvement in SJC. The present post-hoc analysis categorized patientsaccording to PsA duration as follows: <2, 2 to <5, 5 to <10, and ≧10years at baseline. Analyses were conducted on the intention to treatpopulation (ITT population), using non-responder imputation (NRI) forthe ACR scores and last observation carried forward (LOCF) for otherclinical scores.

This post-hoc subanalysis examined patients according to the duration ofPsA at baseline: <2, 2-5, 5-10, and ≧10 years. For patients randomizedto adalimumab, analysis was for the intention-to treat population toWeek 48. While patients were randomized to placebo, analysis was for theintention-to treat population to Week 24 and for patients who receivedopen-label adalimumab, from Weeks 24 to 48. Table 3 shows baselinepsoriasis scores of adalimumab-treated patients grouped by psoriaticseverity.

When data were missing, and for post-escalation results of patients whoescalated to weekly adalimumab dosing on or after Week 36, ACR and PASIresponses were called nonresponder (non-responder imputation), and allother clinical scores were carried forward from the last previousobservation. P values were calculated only for Week 24 results, and notfor open-label extension results (i.e., Week 48)

Baseline data were similar between randomization groups of patientsenrolled in Study G. ACR20/50/70 responses at Week 24 were 57/39/23 forada vs. 15/6/1 for pbo, and at Week 48 were 61/46/31 for patients fromthe ada randomization arm. Among patients in the ada treatment arm,baseline PsA disease duration was <2 years for 26 patients, 2-5 yrs for29 patients, 5-10 yrs for 35 patients and ≧10 yrs for 61 patients (Table11). Within each ada disease-duration group, the ACR20/50/70 responserates, and mean changes in tender joint counts (TJC), swollen jointcounts (SJC), HAQ scores, CRP concentrations and DAS28 scores at Week 24were better than in the corresponding groups of placebo patients (seeTable 11). No significant differences were observed in comparisons ofthese Week 24 measures across the four disease-duration groups.

TABLE 11 Arthritis-related outcomes at Week 24 among ada-treatedpatients by PsA disease duration PsA duration, years (N) <2 (26) 2-5(29) 5-10 (35) ≧10 (61) ACR 20/50/70 46*/38/23† 66/52/28 54/34*/23†59/36/20† Baseline HAQ 0.8 0.9 1.0 1.0 Mean Δ HAQ −0.3* −0.5 −0.3^(†)−0.4 Baseline DAS28 4.7 4.6 4.8 4.9 Mean Δ DAS28 −1.5 −1.7 −1.5 −1.8 *p< 0.05, †p < 0.01, ^(†)not significant; all other results p < 0.001; adavs. pbo (pbo data not shown)

Table 12 shows mean changes in tender and swollen joint counts (TJC,SJC) and CRP concentrations were better than in the corresponding groupsof placebo patients (data not shown).

TABLE 12 Baseline Clinical Characteristics of Adalimumab-TreatedPatients by Disease Duration Overall <2 years 2-5 years 5-10 years ≧10years (N = 151) (n = 26) (n = 29) (n = 35) (n = 61) HAQ (0-3) 1.0 ± 0.60.8 ± 0.6 0.9 ± 0.6 1.0 ± 0.6 1.0 ± 0.7 DAS28 4.8 ± 1.1 4.7 ± 1.1 4.6 ±0.9 4.8 ± 1.2 4.9 ± 1.1 Tender Joint Count 23.9 ± 17.3 26.3 ± 14.7 18.2± 15.1 25.3 ± 19.5 24.9 ± 17.9 (0-78) Swollen Joint 14.3 ± 12.2 15.8 ±14.9 13.4 ± 11.4 14.7 ± 12.4 14.0 ± 11.3 Count (0-76) C-Reactive Protein1.4 ± 2.1 1.0 ± 1.2 1.7 ± 1.8 1.1 ± 1.1 1.6 ± 2.8 (mg/dL) n = 69 n = 13n = 10 N = 18 n = 28 PASI (0-72) 7.4 ± 6.1 7.2 ± 5.6 10.0 ± 11.3 6.9 ±4.3 7.0 ± 4.6 Values are mean ± SD.

ACR20, 50, and 70 responses rates established with adalimumab at Week 24were maintained to Week 48 as shown in Table 13. Similar ACR responsesoccurred in placebo patients upon receiving 24 weeks of open-labeladalimumab.

TABLE 13 ACR Responses at Weeks 24 and 48 Open-label (Week 48) DoubleBlind (Week 24) Placebo/ Placebo Adalimumab Adalimumab Adalimumab (n =162) (n = 151) (n = 147) (n = 151) % Patients with 15 57* 54 61 ACR 20 %Patients with 6 39* 37 46 ACR 50 % Patients with 1 23* 21 31 ACR 70 *p <0.001, adalimumab vs. placebo. Non-responder imputation

ACR20, 50, and 70 response rates with adalimumab were significantlybetter than placebo at Week 24 (Table 14) regardless of PsA diseaseduration.

TABLE 14 Disease Duration <2 years 2-5 years 5-10 years ≧10 years (n =26) (n = 29) (n = 35) (n = 61) % Patients with 46± 66* 54* 59* ACR 20 %Patients with 38* 52* 34± 36* ACR 50 % Patients with 23† 28* 23† 20† ACR70 *p ≦ 0.001, †p < 0.01, ±p < 0.05 vs. placebo (placebo data not shownfor disease duration categories) Non-responder imputation.

In all disease duration categories of patients from the adalimumab armof Study G, ACR response rates were maintained to Week 48 (see Table15).

TABLE 15 ACR Response rates in Adalimumab Treated Patients at Week 48 byBaseline Duration Disease Duration <2 years 2-5 years 5-10 years ≧10years (n = 26) (n = 29) (n = 35) (n = 61) % Patients with 50 66 51 57ACR 20 % Patients with 46 59 37 39 ACR 50 % Patients with 38 38 31 21ACR 70

Variations in ACR responses rates across disease duration groups mayexplained by patient numbers and CRP-related differences (Table 12 andTable 16).

TABLE 16 Mean Change in CRP at Weeks 24 and 48 by Disease DurationDisease Duration <2 years 2-5 years 5-10 years ≧10 years (n = 26) (n =29) (n = 35) (n = 61) Mean Change −0.2 −1.1† −0.4 −1.2* From Baseline atWeek 24 Mean Change −0.5 −1.2 −.04 −1.1 From Baseline at Week 48 *p ≦0.001, †p = 0.002 vs. placebo (not shown), LOCF, LOCF for patients whodiscontinued or whose dosages were increased.

Similar results were obtained as measured by PASI. PASI 50, 75, and 90response rates with adalimumab were significantly better than placebo atWeek 24 (Table 17) regardless of PsA disease duration.

TABLE 17 PASI Response rates in Adalimumab Treated Patients at Week 24by Baseline Duration Disease Duration <2 years 2-5 years 5-10 years ≧10years (n = 13) (n = 10) (n = 18) (n = 28) % Patients with 69± 80* 78*75* PASI 50 % Patients with 46† 60† 72* 57* PASI 75 % Patients with 38±40± 39* 46* PASI 90

In all disease duration categories of patients from the adalimumab armof Study G, PASI response rates were maintained to Week 48 (Table 18).

TABLE 18 PASI Response rates in Adalimumab Treated Patients at Week 48by Baseline Duration Disease Duration <2 years 2-5 years 5-10 years ≧10years (n = 13) (n = 10) (n = 18) (n = 28) % Patients with 54 50 78 71PASI 50 % Patients with 54 40 72 57 PASI 75 % Patients with 38 40 50 50PASI 90

HAQ scores also improved significantly more with adalimumab than placeboin most disease duration categories at Week 24 (placebo data not shown)as shown in Table 19. In all disease duration categories, Week 24improvements in HAQ were maintained to Week 48

TABLE 19 Mean Change in HAQ at Weeks 24 and 48 by Disease DurationDisease Duration <2 years 2-5 years 5-10 years ≧10 years (n = 26) (n =29) (n = 35) (n = 61) Mean Change −0.3† −0.5* −0.3 −0.4* from Baselineat Week 24 Mean Change −0.3 −0.5 −0.3 −0.4 from Baseline at Week 48 *p ≦0.001, †p < 0.05, vs. placebo (placebo data not shown for diseaseduration categories.) LOCF.

Table 16 shows that mean CRP concentrations were decreased from baselinein all disease duration subgroups following 24 weeks of adalimumabtreatment. Mean CRP reductions were also maintained to Week 48.

Adalimumab-treated patients also achieved significant reductions intheir DAS28 scores after 24 weeks of adalimumab treatment compared toplacebo, and maintained these improvements to Week 48 regardless ofduration of PsA at baseline as shown in Table 20.

TABLE 20 Mean Change in DAS28 Scores at Weeks 24 and 48 by DiseaseDuration Disease Duration <2 years 2-5 years 5-10 years ≧10 years (n =26) (n = 29) (n = 35) (n = 61) Mean Change −1.5* −1.7* −1.5* −1.8* fromBaseline at Week 24 Mean Change −1.8 −1.8 −1.6 −2.0 from Baseline atWeek 48

The mean tender and swollen joint counts also declined in all diseaseduration subgroups treated for 24 weeks with adalimumab and theseimprovements were maintained to Week 48 as demonstrated in FIG. 2.

Among patients treated with ada for 48 weeks, ACR responses weremaintained in each disease-duration group, and the mean changes in TJC,SJC, HAQ, CRP, and DAS28 at Week 48 were all equal to or greater thanthe mean changes observed at 24 weeks. Ada was generally safe andwell-tolerated during the blinded phase of Study G and the first 24weeks of the OLE trial.

In conclusion, patients with early and late PsA responded well to ada.Furthermore, disease duration did not have any major impact on thetherapeutic efficacy of ada for arthritis or physical function in PsA.Thus, adalimumab was effective irrespective of the disease duration ofthe subject.

Example 6: Complete Resolution of Arthritis- and Dermatologic RelatedFunctional Loss with Adalimumab in Patients with Psoriatic Arthritis

Psoriatic arthritis (PsA) is a condition associated with significantdisability and functional loss related to both skin and joint componentsof disease. Between 11% and 15% of patients with PsA suffer from longterm disability. The psoriatic component of PsA is associated withsignificant functional loss, including physical complaints withsignificant psychosocial impact. Previous studies in patients with PsAhave shown that administration of adalimumab provides benefits inimproving both joint and psoriatic components of disease.

The object of this study was to assess whether adalimumab at a dose of40 mg every other week (eow) provided complete resolution of loss ofphysical function in patients with PsA versus those on placebo.

The methods of the study have been described previously in Example 1,including the Study G phase III randomized-controlled trial, whereinphysical function was assessed during 24 weeks of treatment. Theinclusion criteria is described above.

Physical function assessment was determined using the Disability Indexof Heath Assessment Questionnaire (HAQ DI), which includes functionalloss and physical function. HAQ DI scores range from 0 to 3, where alower score indicates less functional loss. The Dermatology Life QualityIndex (DLQI) was also used. The DLQI examines changes indermatologic-related functional limitations, and was used with a subsetof patients with BSA >3%. DLQI scores range from 0 to 30, where a lowerscore indicates less impairment.

Statistical analysis was performed between group percentages of patientswith complete resolution of functional loss (HAQ DI or DLQI equal to 0)at weeks 12 and 24. 313 patients were given treatment, 151 receivedadalimumab at a dose of 40 mg every other week, and 162 receivedplacebo. Baseline characteristics were similar between these twotreatment groups, and consistent with moderate to severely active PsA.The mean baseline HAQ DI was 1.0 in both groups, and the mean DLQI totalscore was 8.6 (SD=6.61) in the adalimumab group and 10.3 (SD=7.49) inthe placebo group.

At weeks 12 and 24, significantly more patients in the adalimumab grouphad no functional loss (HAQ DI=0) versus those treated with placebo. Atweek 12, 34% of adalimumab group patients had an HAQ DI=0, whereas only14% of the placebo group had such a score. At week 24, 34% of adalimumabgroup patients had an HAQ DI=0, whereas only 14% of the placebo grouphad such a score.

In a subset of patients with BSA ≧3%, at week 12 significantly morepatients in the adalimumab group had no dermatologic-related functionallimitations (DLQI=0) versus those treated with placebo (40% ada vs. 5%placebo). By week 24, 40% more patients treated with adalimumab 40 mgeow experienced complete resolution of dermatologic-related functionallimitations than patients treated with placebo (45% ada vs. 5% placebo).

In sum, between 30-40% of moderate to severely active PsA patientsexperienced complete resolution of general or dermatologic-relatedfunctional loss when treated with adalimumab 40 mg eow—compared withonly 5% with placebo. Adalimumab reversed debilitating disease effectson physical function early in therapy and provided sustained benefitwith continued treatment.

Example 7: Effectiveness of Adalimumab in Psoriatic Arthritis Patientswith Oligoarticular Arthritis

TNF concentrations are elevated in skin lesions and joints in patientswith PsA. Previous studies have shown that anti-TNF therapy withAdalimumab is efficacious against the arthritis and the skin disease ofPsA. The majority of patients in these previous studies also had active,polyarticular arthritis.

The purpose of this study was to determine whether ACR response rates inthe Study G study differed between patients with oligoarticulararthritis and patients with involvement of ≧5 joints. The inclusion andexclusion criteria for patients in the phase III Study G study isdescribed above. Efficacy was measured using the ACR response and theprimary endpoint was ACR20 at week 12. Data was assessed usingintent-to-treat (ITT) analysis with non-responder imputation. Baselinedisease characteristics are described below in Table 21:

TABLE 21 Baseline Disease Characteristics Placebo Adalimumab EOW 40 mgEOW Characteristic* N = 162 N = 151 Swollen Joint Count (0-76) 14.3 ±11.1 14.3 ± 12.2 Tender Joint Count (0-78) 25.8 ± 18.0 23.9 ± 17.3C-Reactive Protein (mg/dl) 1.4 ± 1.7 1.4 ± 2.1 HAQ (0-3) 1.0 ± 0.7 1.0 ±0.6 n = 69† n = 70† PASI (0-72) 8.3 ± 7.3 7.4 ± 6.1 (Range) (0.4-40.9)(0.2-38.0) PGA (“Clear” or “Almost 1 (1.4%) 1 (1.4%) Clear”) *Meanvalues ± SD, except percentages †Patients with BSA ≧3%; N + 69 for PASIscores of adalimumab-treated patientsThe percentage of polyarthritis patients with oligoarthritis (TJC <5 orSJC <5) was as follows:

Placebo (n=162)

-   -   9.3% (n=15) had SJC <5 only    -   1.9% (n=3) had TJC <5 only    -   1.2% (n=2) had both

Adalimumab (n=151)

-   -   10.6% (n=16) had SJC <5 only    -   1.3% (n=2) had TJC <5 only    -   5.3% (n=8) had both

At week 12, the ACR20 response rate for the whole cohort was higher foradalimumab than placebo (58% vs. 14%; p<0.001) and at week 24 thisdifference was maintained for all levels of ACR responses (ACR 20/50/70adalimumab, 57/39/23; placebo 15/6/1). In patients with TJC <5 or SJC <5at baseline, the ACR response rates for patients receiving adalimumabwere comparable to those of the overall adalimumab cohort, and higherthan those of patients with TJC <5 or SJC <5 treated with placebo.Percentages of patients having ACR 20/50/70 responses at week 12 forpatients with TJC <5, included the following: 0%/0%/0% placebo (n=5) vs.70%*/30%/10% adalimumab (n=10) (*p<0.05 vs. placebo, non-responderimputation). Percentages of patients having ACR 20/50/70 responses atweek 24 for patients with TJC <5, included the following: 20%/0%/0%placebo (n=5) vs. 63%*/38%*/21% adalimumab (n=10) (non-responderimputation). Percentages of patients having ACR 20/50/70 responses atweek 12 for patients with SJC <5, included the following: 18%/0%/0%placebo (n=17) vs. 70%*/30%/10% adalimumab (n=24) (*p<0.01 vs. placebo,non-responder imputation). Percentages of patients having ACR 20/50/70responses at week 24 for patients with SJC <5, included the following:18%/6%/0% placebo (n=17) vs. 58% †/42% †/29% † adalimumab (n=24)(†p<0.05 vs. placebo, non-responder imputation).

The baseline HAQ scores for patients with TJC <5 at baseline were 0.6for both the placebo and adalimumab groups respectively. The baselineHAQ scores for patients with SJC <5 at baseline were 1.0 and 0.9 for theplacebo and adalimumab groups respectively. There was an overallimprovement in the HAQ scores in patients receiving adalimumab.

Mean changes in HAQ scores at week 12 and week 24 for patients with TJC<5 included week 12: −0.1 placebo (n=5) and -0.3 adalimumab (n=10), andat week 24: 0.0 placebo (n=5) and -0.3 adalimumab (n=10). Mean changesin HAQ scores at week 12 and week 24 for patients with SJC <5 includedweek 12: −0.1 placebo (n=17) and -0.4 adalimumab (n=24), and at week 24:0.0 placebo (n=17) and -0.5* adalimumab (n=24) (*p<0.01 vs. placebo,non-responder imputation).

In sum, this study showed that in the subset of patients witholigoarticular disease, efficacy appeared to be comparable to that seenin the overall study population, which was dominated by patients withactive polyarticular disease. Adalimumab was effective at treatingpatients with oligoarticular arthritis.

Example 8: Enhanced Efficacy Following Dose Escalation in Patients withModerate to Severe Psoriatic Arthritis Who have Subtherapeutic Responseto Adalimumab Eow Dosing

This study was based in part on Study G, a double-blind,placebo-controlled, 24-week (wk) Phase III study of adalimumab 40 mg eowin patients (pts) with active PsA (≧3 swollen and ≧3 tender joints).Study G, as described above and in Mease et al. ((2005) Arthritis Rheum52: 3279-3289, incorporated herein by reference), demonstratedclinically meaningful and statistically significant improvement in skinand joint outcomes at Wk 24 (ACR20 of 57%, PASI75 of 59% in adalimumabpatients vs. ACR20 of 15%, PASI75 of 1% in placebo patients). Patientscompleting Study G and a smaller 12-wk, Phase III PsA study (Study X),were eligible to enroll in an open-label extension study (OLES). Thisexample describes the efficacy and safety in patients who startedadalimumab 40 mg weekly in the OLES.

Efficacy and safety data were collected from the earlier randomized,placebo-controlled, double blind trials, i.e., Studies G and X. Thedesign of Study X was as follows. After an initial screening period, 100patients were randomized. 51 patients received 40 mg of Adalimumab(ada)every other week, for a 12 week period, and 49 patients received placeboevery other week for a 12 week period. The study was conducted in adouble blind manner. Statistical analysis was conducted at week 12.

In Study G, patients were randomized 1-to-1 to receive placebo or ada 40mg eow, administered subcutaneously. Patients completing the Phase IIIstudies (Study G and Study X), were eligible to continue in anopen-label extension study (described in this example) in which allpatients received active therapy (ada 40 mg eow). Placebo patients wereswitched to adalimumab 40 mg eow when they enrolled in the OLES, andadalimumab patients continued on their previous regimen.

Inclusion criteria for patients included in this study included: swollenand tender joints; inadequate response to DMARD or NSAID therapy; ahistory of psoriasis; and a minimum age of 18. Patients with prioranti-TNF therapy were excluded.

Efficacy measures included: ACR response criteria (co-primary endpoint:ACR20 response at Week 12); tender and swollen joint counts; healthassessment questionnaire disability index (HAQ); and psoriasis area andseverity index (PASI) in patients enrolled from Study G with significantpsoriasis at study entry (BSA). After 12 wks in the OLES, those patientswith less than 20% improvement in both swollen and tender joint countscompared to Wk 0 of the Phase III study were allowed to increase theiradalimumab dose to 40 mg wkly. Skin and joint outcomes, along withsafety, were assessed up to 36 wks after dose escalation.

Results

Week 12 of this study was the first time point at which patients withsubtherapeutic response to adalimumab were eligible for dosageescalation. Weekly dosing was allowed after week 12 only in thosepatients with a 0% improvement in tender joint count and swollen jointcount relative to respective baseline values from Study G or the smallerstudy. The observed responses at week 12 are shown in Table 22. As canbe seen in Table 22, at week 12 of this OLES study, 47% ofadalimumab-treated and 58% of placebo/adalimumab-treated patients whoenrolled from Study G had achieved ACR20 responses. A majority of theskin-evaluable patients enrolled from Study G had achieved PASI 50responses by week 12 as well. ACR20 responses at week 12 of the OLESstudy for patients enrolled from Study X were similar to those ofpatients enrolled from Study G.

TABLE 22 Overall Joint and Skin Responses Prior to Dosage Escalation forPatients Enrolling from Study G: Observed Responses at Week 12 of OLESAfter 36 weeks of adalimumab After 12 weeks 40 mg eow adalimumab 40 mgeow (adalimumab arm) (placebo→adalimumab arm) (n = 136) (n = 143) ACR20(%) 58 47 ACR50 (%) 39 31 ACR70 (%) 30 14 Skin-evaluable patients (≧3%BSA) (n = 56) (n = 61) PASI 50 (%) 73 56 PASI 75 (%) 62 42 PASI 90 (%)42 27

Observed Analysis.

The number of patients whose dosages were increased to weekly dosing inthe OLES study are shown below in Table 23.

TABLE 23 Received Received placebo in Received adalimumab adalimumabStudy G or Study X eow in Study G eow in Study X Week 12 26 14 6 Week 242 1 1 Week 36 2 1 0 *Week 12, 24, and 36 are relative to start ofopen-label treatment

Baseline demographics and disease severity characteristics were similarbetween patients whose dosages were and were not increased with theexception of the number of tender joints at baseline. The baselinedemographics and disease characteristics of the patients in this studycan be seen in Table 24.

TABLE 24 Baseline Demographics and Disease Characteristics PatientsPatients whose whose dosages dosages were not were increased increasedCharacteristic* (n = 53) (n = 342) Age (years) 48.8 ± 8.4  49.1 ± 12.1 %Male 49 56 % Caucasian 94 96 Body weight (kg) 90.7 ± 23.3 86.3 ± 18.8Rheumatoid Factor Negative (%) 93 89 Duration of Psoriatic Arthritis 8.6± 8.3 9.1 ± 8.3 (years) Duration of Psoriasis (years) 17.0 ± 13.5 16.9 ±12.1 No. of previous DMARDs 1.5 ± 1.1 1.6 ± 1.2 % MTX Use 43 50 BaselinePASI  8.9 ± 9.3†  8.1 ± 6.9† Swollen Joint Count 17 ± 12 14 ± 12 TenderJoint Count 31 ± 20  22 ± 18‡ C-Reactive Protein (mg/dL) 1.6 ± 1.7 1.3 ±1.9 HAQ 1.1 ± 0.7 0.9 ± 0.6 *Mean values ± SD except percentages. †N =22 and N = 106 in patients whose dosages were and were not increased,respectively. ‡p < 0.01 vs. patients whose dosages were increased.

ACR response rates in patients whose dosages were increased to weeklydosing had rapid onset and were maintained to 36 weeks after dosageescalation. ACR20 responses exceeded 0% for patients who increased theirdosages because dosage escalation was based on swollen joint count andtender joint count improvement relative to baseline values of Study G orStudy X, while ACR evaluations were relative to the first dose ofadalimumab. FIG. 3 shows the ACR responses after dosage escalation overtime.

FIG. 4 is a graphical representation of the PASI improvement in patientswhose dosages were increased. As can be seen in this figure, the meanpercentage PASI improvement was 23% at 36 weeks after dosage escalation.

The PASI and PGA “Clear”/“Almost Clear” response rates at selected timepoints after dosage escalation are shown below in Table 25.

TABLE 25 Week 12 Week 24 Week 36 (n = 20) (n = 16) (n = 7) PASI 50 (%)60 69 71 PASI 75 (%) 35 69 71 PASI 90 (%) 25 38 71 PASI 100 (%) 10 19 43PGA “Clear”/ 32 45 45 “Almost Clear” (%)Observed values. Weeks 12, 24, and 36 are relative to start of dosageescalation. N=22 for percentages of patients with PGA “Clear”/“AlmostClear” at weeks 12-36.

Of the total 382 patients, 53 (14%) started adalimumab 40 mg weekly inthe OLES. Among them, 45% were concomitantly taking methotrexate,compared to 50% in patients not undergoing dose escalation. Skin andjoint outcomes observed prior to and 12 wks after dose escalation areshown below (Table 26):

TABLE 26 Prior to dose 12 wks after dose escalation escalation ACR20/50/70 (% responders) 11/2/0 41/22/11 PASI 50/75/90 (% responders)55/18/14 60/35/25 PGA Clear/Almost Clear (%) 10 32Joint and skin improvements were sustained up to 36 wks after doseescalation.

Four patients experienced a serious adverse event (AE), including 1serious infectious AE, after dose escalation. One patient discontinuedfrom the study due to an AE. The four serious adverse events experiencedby patients undergoing dosage escalation included: diverticulitis,appendicitis, salmonella infection, and pancreatitis. These seriousadverse events were considered by the investigators to be probablyunrelated to the adalimumab treatment. Table 27 shows the common adverseevents that occurred ≧5% in those patients whose dosages were increased.

TABLE 27 On or after increase in adalimumab dosage from eow to weekly N= 53 N (%) Any AE (adverse event) 31 (58.5) Any SAE (serious adverseevent) 4 (7.5) Upper Respiratory Tract Infection NOS 1 (1.9)Nasopharyngitis 1 (1.9) Headache NOS 2 (3.8) Cough 0 (0.0) Injectionsite reaction NOS 0 (0.0) Liver Function Test NOS abnormal 1 (1.9)Psoriatic arthropathy aggravated 2 (3.8) Contusion 1 (1.9)Pharyngolaryngeal Pain 1 (1.9) *NOS = not otherwise specified

In sum, approximately 85% of PsA patients treated with adalimumab eowhad a sufficiently satisfactory clinical response and did not requiredose escalation. In patients whose dosages were increased fromadalimumab eow to weekly, adalimumab was efficacious against skin andjoint disease. Adalimumab was also well tolerated in the subpopulationof patients whose dosages were escalated.

Example 9: Adalimumab is Efficacious in Treating the Skin Disease ofPatients with PsA Who have Mild to Severe Baseline Skin Involvement:Subanalysis by Severity of Psoriasis

The purpose of this study was to examine skin outcomes in patientsubgroups with mild to moderate and moderate to severe psoriasis atbaseline. Study G was a double-blind, placebo-controlled Phase III studyof adalimumab in patients with active PsA (≧3 swollen and ≧tenderjoints) as described above. Patients were stratified by methotrexate use(yes/no) and degree of psoriasis (<3% and ≧3% BSA involvement (skinevaluable)) and randomized to adalimumab 40 mg eow or placebo for 24weeks. PASI and PGA were measured for patients with ≧3% BSA. Patientswere subgrouped by baseline PGA (a static composite of plaqueevaluation, scaling and erythema) as mild to moderate or moderate tosevere. Skin efficacy outcomes were analyzed post-hoc on an ITT, NRIbasis for each subgroup.

Efficacy measures included: ACR response criteria (co-primary endpoint:ACR20 response at Week 12); PASI in patients with significant psoriasisat study entry (≧3% BSA); and PGA of psoriasis. The post-hoc subanalysisexamined patients according to the severity of psoriasis at baseline:PGA of mild to moderate vs. PGA of moderate to severe. Weekly adalimumabdosing was allowed on or after Week 36 in patients with <20% improvementin tender joint count and swollen joint count.

313 patients (151 adalimumab, 162 placebo) enrolled in Study G, withsimilar baseline data between groups. As described in Table 1 above,baseline demographics and disease characteristics were comparable inpatients with mild to moderate and with moderate to severe psoriasis atbaseline with the exception of the percentages of male patients (47%placebo-treated and 53% adalimumab-treated male patients in the mild tomoderate psoriasis subgroup, and 62% placebo-treated and 63%adalimumab-treated male patients in the moderate to severe psoriasissubgroup).

PASI was evaluated for 138 patients (69 adalimumab, 69 placebo). As canbe seen in Table 28, baseline PASI and DLQI scores were comparable amongthe placebo and adalimumab-treated subgroups of patients.

TABLE 28 Placebo Adalimumab 40 mg eow Mild to Moderate to Mild toModerate to Moderate Severe Moderate Severe Characteristics PsoriasisPsoriasis Psoriasis Psoriasis Mean PASI ± SD n = 30 n = 39 n = 30 n = 39(0-72) 4.0 ± 2.4 11.6 ± 8.0 4.4 ± 2.8  9.8 ± 6.8 Mean DLQI ± SD n = 30 n= 38 n = 29 n = 37 9.9 ± 7.9 10.5 ± 7.3 5.6 ± 4.3 11.0 ± 7.1

Overall, ACR20/50/70 and PASI 50/75/90 responses at Week 24 were57/39/23 and 75/59/42 for adalimumab versus 15/6/1 and 12/1/0 forplacebo. The overall PASI 50/75/90/100 responses at Week 24 were75/59/42/29 adalimumab (n=69) and 12/1/0/0 placebo (n=69).

Table 29 shows the PASI responses at Weeks 12 and 24 by diseaseseverity, including mild to moderate and moderate to severe. At Week 24,PASI 50/75/90/100 in mild to moderate psoriasis patients were77/60/40/33 (adalimumab) and 7/0/0/0 (placebo) (p<0.001); in moderate tosevere psoriasis patients, PASI 50/75/90 were 74/59/44 (adalimumab) and15/3/0 (placebo) (p<0.001).

TABLE 29 PASI Responses at Weeks 12 and Weeks 24 by Disease SeverityWeek 12 Week 24 Mild- Moderate- Mild- Moderate- moderate severe moderatesevere (n = 30) (n = 39) (n = 30) (n = 39) PASI 50 (%) 77* 69* 77* 74*PASI 75 (%) 50* 49* 60* 59* PASI 90 (%) 27  33* 40* 44* PASI 100 (%) 13 8 33* 26* *p ≦ 0.001, †p = 0.005 vs. placebo (placebo data not shown)Non-responder imputation.

Overall PASI responses, and responses for each subgroup at week 24, areshown below in Table 30:

TABLE 30 Overall PASI responses at Week 24 Mild-moderate byModerate-severe by Overall baseline PGA baseline PGA Adalimumab PlaceboAdalimumab Placebo Adalimumab Placebo (n = 69) (n = 69) (n = 39) (n =39) (n = 30) (n = 30) PASI 50 (%) 75* 12 77* 7 74* 15 PASI 75 (%) 59* 160* 0 59* 3 PASI 90 (%) 42* 0 40  0 44* 0 PASI 100 (%) *P < 0.001adalimumab vs. placebo

In each disease severity group, at Week 24, a PGA score of “Clear” or“Almost Clear” was significantly more frequent with adalimumab-treatedthan placebo-treated patients. The percentage of patients with PGA“Clear” or “Almost Clear” at Week 24 included 23% placebo (n=30) vs.73%* adalimumab (n=30) for mild to moderate subgroup and 0% placebo(n=33) vs. 55%* adalimumab (n=40) for moderate to severe (*p<0.001 vs.placebo, non-responder imputation).

At Week 24, patients treated with adalimumab also achieved animprovement in their quality of life, as measured by DLQI. The meanchange in DLQI from baseline to Week 24 in patients in the Mild toModerate subgroup was −0.4 placebo (n=30) vs. −3.2 adalimumab (n=29),and for the Moderate to Severe subgroup the mean change was −1.0 placebo(n=36) vs. −8.2* adalimumab (n=37) (*p<0.001 vs. placebo, LOCF).Furthermore, at week 24, in each disease severity group, there weresubstantial percentages of adalimumab-treated patients who achieved aDLQI of 0. The percentage of patients with a DLQI equal to 0 at Week 24for the mild to moderate subpopulation was 7% placebo (n=30) vs. 40%adalimumab (n=30) and for the moderate to severe subpopulation 3%placebo (n=37) vs. 40% adalimumab (n=40).

Rates of individual adverse events and serious adverse events werecomparable between adalimumab and placebo. Table 31 shows the commonadverse events that occurred ≧5% at Week 24.

TABLE 31 Common Adverse Events Adalimumab Placebo eow 40 mg eow N = 162N = 151 N (%) N (%) Any AE (adverse event) 130 (8.20 122 (80.8) Any SAE(serious adverse event) 7 (4.3) 5 (3.3) Upper Respiratory TractInfection NOS 24 (14.8) 19 (12.6) Nasopharyngitis 15 (9.3) 15 (9.9)Headache NOS 14 (8.6) 9 (6.0) Injection site reaction NOS 5 (3.2) 10(6.6) Hypertension NOS 5 (3.1) 8 (5.3) PsA aggravated 11 (6.8) 5 (3.3)Psoriasis aggravated 10 (6.2) 3 (2.0) Arthralgia 9 (5.6) 3 (2.0)Diarrhea NOS 9 (5.6) 3 (2.0) *NOS = not otherwise specified

In sum, adalimumab was efficacious against PsA skin disease and improveddermatology-specific quality of life in patients whose psoriasis atbaseline, as measured by PGA, ranged from mild to moderate, or moderateto severe. Furthermore, adalimumab had an acceptable safety profile andwas well-tolerated during 24 weeks of treatment in Study G.

Example 10: PASI 100 is Associated with Better Dermatology-SpecificPatient Reported Outcomes Compared with PASI 75-99 in Adalimumab-TreatedPatients with Psoriatic Arthritis: Subanalysis of PsA Study G

The following describes a sub-analysis of Study G, which was the largestrandomized, double-blind, placebo-controlled trial to date of a TNFantagonist in psoriatic arthritis (PsA). Patients who participated inthe study predominantly had long-standing, polyarticular disease, andapproximately half used methotrexate (MTX) during the trial. The overallconclusion of the study was that 24 weeks of treatment with adalimumabprovided significant improvements in skin disease, arthritis, andquality of life for patients with moderate to severe PsA who had failedNSAID therapy

The object of the following study was to determine whether patients whoachieved a PASI 100 response in Study G, a Phase III study of adalimumabin patients with psoriatic arthritis (PsA), had superiordermatology-specific patient reported outcomes compared with patientswho achieved PASI 75-99 responses

For the present analysis, DLQI scores were compared among patientsclassified post hoc by their level of skin response at Week 24 (PASI<50, 50-74, 75-99, or 100). Analyses were restricted to observed datafrom patients with ≧3% BSA involvement at baseline. Efficacy outcomemeasures for the present analyses included: Psoriasis Area and Severityindex (PAST); Dermatology Life Quality Index (DLQI)—lower scoreindicates better health status; and American College of Rheumatologyresponse rate (for arthritis).

DLQI scores were determined for patients grouped post-hoc by thecategory of level PASI response from baseline to Week 24: PASI <50; PASI50-74; PASI 75-99; and PASI 100. Analyses were restricted to observeddata from patients with ≧3% BSA involvement at baseline, and DLQI andPASI scores recorded at baseline and Week 24

A total of 313 patients received treatment with adalimumab or placebo inStudy G (Tables 1 and 32). In the placebo arm and the adalimumab arm, 59patients each had >3% BSA involvement with psoriasis, completed 24 weeksof blinded therapy, and had PASI and DLQI scores available from baselineand Week 24 (Table 33). Baseline demographics and diseasecharacteristics were comparable for these 59 placebo and 59 adalimumabpatients.

TABLE 32 Baseline Demographics and Disease Severity CharacteristicsAdalimumab Placebo 40 mg eow Characteristics* (N = 162) (N = 151) Age,years 49.2 ± 11.1 48.6 ± 12.5 Males, % 55 56 Caucasian, % 94 97 Bodyweight, kg 85.5 ± 16.5 86.0 ± 20.6 Psoriasis duration, years 17.1 ± 12.617.2 ± 12.0 Psoriatic arthritis 9.2 ± 8.7 9.8 ± 8.3 duration, yearsRheumatoid factor 90 89 negative, % Patients taking MTX at 50 51baseline†, % BSA ≧3% skin 70 70 involvement, n PASI score‡§ 8.3 ± 7.27.4 ± 6.0 DLQI‡∥ 10.3 ± 7.5  8.6 ± 7.4 *Mean values ± SD, except forpercentages or BSA ≧3% skin involvement; †Mean MTX dosage of 17.1 mg/wk;‡Patients with ≧3% BSA skin involvement; §n = 69 for both placebo andadalimumab groups; ∥n = 68 for placebo, n = 66 for adalimumab

TABLE 33 Baseline Characteristics by PASI Response in Adalimumab-TreatedPatients PASI <50 PASI 50-74 PASI 75-99 PASI 100 Characteristics* (N =10) (N = 8) (N = 22) (N = 19) Age, years 51.2 ± 12.0 49.0 ± 14.2 48.7 ±16.6 49.3 ± 13.4 Males, % 60 38 59 58 Caucasian, % 100  100  96 95 Bodyweight, kg 88.7 ± 21.5 96.8 ± 36.6 93.6 ± 23.3 81.9 ± 17.4 Psoriasisduration, 21.0 ± 16.4 21.9 ± 13.6 14.0 ± 8.2  17.9 ± 13.2 yearsPsoriatic arthritis 10.8 ± 11.3 10.2 ± 11.5 8.5 ± 6.8 11.3 ± 9.4 duration, years Rheumatoid factor 90 88 86 95 negative, % Patientstaking MTX at 30 25 55 47 baseline†, % PASI score 6.1 ± 5.7 10.0 ± 6.5 7.3 ± 4.5 6.2 ± 3.4 DLQI 9.4 ± 4.7 10.5 ± 7.9  9.5 ± 6.7 6.8 ± 6.7 Anyprevious DMARD 80 63 96 84 use, % Swollen joint count 19.9 ± 13.8 14.6 ±11.0 15.0 ± 14.3 10.9 ± 8.9  Tender joint count 28.2 ± 19.7 22.5 ± 12.426.2 ± 22.7 18.5 ± 17.0 CRP (mg/L) 1.4 ± 1.4 1.5 ± 1.4 1.8 ± 3.4 1.3 ±1.5 HAQ DI 1.3 ± 0.7 1.0 ± 0.7 1.3 ± 0.6 0.8 ± 0.7 Patients with >3% BSAinvolvement with psoriasis who completed 24 weeks of blinded therapy andhad PASI and DLQI scores available from baseline and Week 24. *Meanvalues ± SD, except for percentages; †Mean MTX dosage of 17.1 mg/wk forall patients.

At Week 24, PASI 75 responses were observed in 69% of patients treatedwith adalimumab (including 32% PASI 100) compared with 2% with placebo(Table 34).

TABLE 34 PASI Response Rates at Week 24 Adalimumab (n = 59) Placebo (n =59) PASI <50 (%) 17 85 PASI 50-74 (%) 14 14 PASI 75-99 (%) 37 2 PASI 100(%) 32 0

Restricted to patients in Study G who had PASI and DLQI data at baselineand Week 24. Observed values.

Arthritis improvement was greatest in patients with PASI 100 responsesat Week 24 (Table 35).

TABLE 35 ACR Response Rates for Adalimumab-Treated Patients by Level ofPASI Response at Week 24 ACR20 ACR50 ACR70 PASI <50 (%) 50 20 10 (n =10) PASI 50-74 (%) 50 13 0 (n = 8) PASI 75-99 (%) 50 41 32 (n = 22) PASI100 (%) 74 58 37 (n = 19)

Restricted to patients in Study G who had PASI and DLQI data at baselineand Week 24. Observed values.

At Week 24, the mean HAQ DI score was lowest in adalimumab-treatedpatients with PASI 100 responses (Table 36).

TABLE 36 Mean HAQ DI Scores for Adalimumab-treated Patients by PASIResponse Rates at Week 24 Mean Change in Mean HAQ DI Mean HAQ DI at HAQDI at Scores Baseline Week 24* PASI <50 (%) 0.8 1.3 −0.5 (n = 10) PASI50-74 (%) 0.6 1.0 −0.4 (n = 8) PASI 75-99 (%) 0.7 1.3 −0.6 (n = 22) PASI100 (%) 0.3 0.8 −0.4 (n = 19) Observed values. *Minimum ClinicallyImportant Difference = −0.30 for PSA (Mease, P J, et al. Ann Rheum Dis.2004; 63: Suppl 1: 391-2); and −0.22 for rheumatoid arthritis (GoldsmithC., et al., J Rheumatol. 1993; 20: 561-5).

At Week 24, the mean DLQI scores were lowest and the most improved inadalimumab-treated patients with PASI 75-99 and PASI 100 responses(Table 37)

TABLE 37 Mean DLQI Scores for Adalimumab-treated Patients by PASIResponse Rates at Week 24 Mean Change in Mean DLQI Mean DLQI at DLQI atWeek Scores Baseline 24* PASI <50 (%) 5.6 9.4 −3.8 (n = 10) PASI 50-74(%) 7.1 10.5 −3.4 (n = 8) PASI 75-99 (%) 1.3 9.5 −8.2 (n = 22) PASI 100(%) 0.2 6.8 −6.6 (n = 19) *Minimum Important Difference = −5.0; ShikarR., et al., Health Qual Life Outcomes. 2006; 4: 71. Observed values.

At Week 24, a DLQI score of zero or 1 was achieved by 95% of patientswith PASI 100 response, compared with 68% of PASI 75-99 responders(Table 38).

TABLE 38 DLQI Scores for Adalimumab-treated Patients by PASI ResponseRates at Week 24 DLQI = 0 DLQI = 1 DLQI = 2 DLQI ≧ 3 PASI <50 (%) 18 0 082 (n = 10) PASI 50-74 (%) 30 10 30 30 (n = 8) PASI 75-99 (%) 36 32 1418 (n = 22) PASI 100 (%) 75 20 0 5 (n = 19)

At Week 24, the DLQI score was >1 in only 5% of patients with a PASI 100response, compared with 32%, 60%, and 82% of patients with PAST 75-99,50-74, and <50 responses (Table 38). Table 39 shows the DLQI questionsthat accounted for a score >0 in Adalimumab treated patients at week 24.

TABLE 39 DLQI Questions Accounting for Score >0 in Adalimumab-TreatedPatients at Week 24 PASI 100 PASI 75-99 Responders Responders with DLQIwith DLQI Score of >0, Score of >0, DLQI Question Topic n (%) n (%) 1.Skin itchy, sore, painful, or 4 (21) 10 (46) stinging? 2. Degree towhich embarrassed or 0 2 (9) self-conscious because of skin? 3. Degreeto which skin interfered 0 1 (4) with daily activities, e.g., shoppingor looking after your home or garden. 4. Degree to which skin influenced0 2 (9) the clothing choice? 5. Degree to which skin affected 0 2 (9)social or leisure activities? 6. Degree to which skin made 0 2 (9)playing sports difficult? 7. Degree to which skin is a 0 2 (9) problemat work or studying? 8. Degree to which skin brings 0 1 (4) problemswith partner or close friends or relatives? 9. Degree to which skincaused any 0 0 sexual difficulties? 10. Degree to which treatment for 04 (18) skin has been problem, e.g., making home messy, or by taking uptime?

In sum, the results showed that at Week 24, PASI 75-99/100 responserates were 2%/0% for the placebo group and 34%/31% for the adalimumabgroup. Adalimumab-treated patients with PASI <50 (n=11), 50-74 (n=10),75-99 (n=22), or 100 (n=20) had mean DLQI scores (lower score indicatesbetter health status) of 5.9, 5.8, 1.3, and 0.4, respectively; amongthose with baseline and Week 24 DLQI scores, mean reductions in DLQIfrom baseline were 3.8, 3.4, 8.2, and 6.6, respectively (MID [minimumimportant difference] for DLQI estimated at 5.0). At Week 24,18%/30%/36%/75% of patients with PASI <50/50-74/75-99/100 had a DLQIscore of 0, respectively; 0%/10%/32%/20% had a DLQI score of 1,respectively; 0%/30%/14%/0% had a DLQI score of 2, respectively; and82%/30%/18%/5% had a DLQI score of ≧3, respectively.

In conclusion, adalimumab treatment of patients with PsA providedsustained and clinically meaningful improvement. Results from thispost-hoc subanalysis suggest that achievement of PASI 100 represents aclinically meaningful incremental benefit above the achievement of PASI75-99. In post-hoc analyses of Study G, outcomes of arthritis, physicalfunction, and dermatology-related quality of life were better at Week 24in patients with PASI 100 responses compared with PASI 75-99 responders.At Week 24, a DLQI score of zero or 1 was achieved by 95% of patientswith PASI 100 response, compared with 68% of PASI 75-99 responders. ADLQI >1 was rare in patients with a PASI 100 response (5%).

Example 11: Safety and Efficacy of Adalimumab in the Treatment ofPatients with Psoriatic Arthritis Who Had Failed Disease-ModifyingAntirheumatic Drug Therapy

The object of the following study was to demonstrate the safety andefficacy of adalimumab for the treatment of moderately to severelyactive psoriatic arthritis (PsA) in a subpopulation of patients with aninadequate response to disease-modifying antirheumatic drugs (DMARDs).

Study Design

A double-blind, Phase III, randomized placebo-controlled, multicenterstudy was conducted to demonstrate the safety and efficacy of adalimumabin the treatment of moderately to severely active PsA in patients whohad had an inadequate response to DMARD therapy. Following a screeningperiod of up to 14 days, patients were stratified by DMARD use atbaseline (yes/no), and then randomized in a 1:1 ratio to receive asubcutaneous injection of adalimumab 40 mg every other week (eow) orplacebo for 12 weeks. Patients were randomized in blocks of 4 using aninteractive voice response system. Patients who completed the blindedphase could elect to receive open-label therapy with adalimumab 40 mgeow, the first 12 weeks of which are reported here. Study drug wasprovided in pre-filled syringes containing a 0.8-ml solution ofadalimumab (50 mg/ml) or matching placebo (Abbott Laboratories, AbbottPark, Ill.). Study visits occurred at baseline and Weeks 2, 4, 8, 12,14, 18, and 24 for safety and efficacy assessments.

The primary efficacy measure was a 20% improvement in American Collegeof Rheumatology (ACR20) core criteria at Week 12. Secondary efficacymeasures included the modified Psoriatic Arthritis Response Criteria(PsARC) and assessments of disability, psoriatic lesions, and quality oflife. For missing data, nonresponder imputation was used for ACR andPsARC scores and last observation carried forward for other measures.

The study was conducted at 16 sites in Canada and the United States. Theprotocol was approved at each site by an independent ethics committee orinstitutional review board and was conducted in accordance with theInternational Conference on Harmonization Good Clinical Practicestandards; Food and Drug Administration regulations governing clinicalstudy conduct; ethical principles originating from the Declaration ofHelsinki (1989 revision); and all applicable local laws and customs. Allparticipants provided written informed consent after the nature andpurpose of the study had been explained and before any study procedurewas initiated.

Patients

Eligible patients were male or female, at least 18 years of age, and ingenerally good health based on medical history, physical examination,laboratory profile, chest radiograph, and a 12-lead electrocardiogram.At study entry, patients were required to have had ≧3 swollen joints and≧3 tender or painful joints, and either an active cutaneous lesion ofchronic plaque psoriasis or a documented history of chronic plaquepsoriasis diagnosed by the investigator or a dermatologist. All patientsenrolled in the study were receiving concomitant DMARD therapy or had ahistory of DMARD therapy with an inadequate response, as defined by theinvestigator. Oral corticosteroids were allowed during the trial if thedosage did not exceed the equivalent of prednisone 10 mg/day and hadbeen stable during the 4 weeks preceding the baseline visit. Concomitanttreatment with MTX or other DMARDs, with the exception of cyclosporineand tacrolimus (oral or topical) received within 4 weeks of the baselinevisit, was allowed if the patient had received a minimum of 3 months oftherapy and the dosage had been stable during the 4 weeks preceding thebaseline visit. The maximum allowable MTX dosage was 30 mg/week. Apurified protein derivative skin test was required for all participants.For patients with evidence of a previous tuberculosis infection, adocumented history of treatment for latent tuberculosis was required, orsuch treatment had to have been initiated before the first dose of studydrug.

Patients were excluded if they had a history of: previous anti-TNFtherapy; intravenous infusions or intra-articular injections ofcorticosteroids within 4 weeks of baseline; topical psoriasis therapies(e.g., keratolytics, coal tar, anthralin) within 2 weeks of baseline(although medicated shampoos and low-potency topical steroid use on thepalms, soles of the feet, axilla, and groin area were allowed);ultraviolet A (UVA) phototherapy, including psoralen and UVA, or use ofa tanning booth within 2 weeks of the baseline visit; or oral retinoidswithin 4 weeks of the baseline visit; alefacept or siplizumab within 12weeks, or any other biologic or investigational therapy within 6 weeksof the baseline visit. They were also excluded based on current use orlikely need for antiretroviral therapy.

Patients with persistent or severe infections or a history of activetuberculosis, or who had an active nonpsoriatic skin disease that couldinterfere with the assessment of target lesions were also excluded.Additional exclusion criteria were a significant history of cardiac,renal, neurologic, psychiatric, endocrinologic, metabolic, or hepaticdisease; neurologic symptoms suggestive of central nervous systemicdemyelinating disease; and a history of malignancy other than carcinomain situ of the cervix or adequately treated non-metastasic squamous orbasal cell skin carcinoma.

Measures of Efficacy and Safety

The primary efficacy variable was the ACR20 response rate at Week 12(Felson et al. Arthritis Rheum 1995; 38:727-35.). The total number ofassessed joints was 78 for the tender joint count (TJC) and 76 for theswollen joint count (SJC) (Mease P J, et al. Arthritis Rheum 2005;52:3279-89). Joints or regions examined were those routinely examined inRA plus the first carpal metacarpal phalangeal joints (n=2) and thedistal interphalangeal joints of the toes (n=8). Hips were excluded fromthe SJC. Patients were evaluated for dactylitis of the hands and feet(total score 0-60, with each digit rated 0 [absent] to 3 [severe]), andenthesitis of the proximal insertion of the Achilles tendon and plantarfascia (total score 0-4, with each insertion rated 0 [enthesitis absent]or 1 [enthesitis present]). Other efficacy measures included patient'sassessment of pain during the previous week, patient's global assessmentof disease activity during the previous 24 hours, and physician's globalassessment of disease activity (current PsA activity), each using avisual analog scale (VAS) of 0-100 mm (Felson et al., supra). Secondaryefficacy measures of arthritis and QOL included the ACR50 and ACR70response rates, the modified Psoriatic Arthritis Response Criteria(PsARC) (Clegg D O, et al. Arthritis Rheum 1996; 39:2013-20; Mease P J,et al. Arthritis Rheum 2004; 50:2264-72); the disability index of theHealth Assessment Questionnaire (HAQ DI) score (Fries J F, et al, JRheumatol 1982; 9:789-93); the Short Form 36 Health Survey (SF-36) andits Physical and Mental Component Summary (PCS and MCS) scores (Fries etal, supra); and the 13-item fatigue scale of the Functional assessmentof Chronic Illness Therapy (FACIT-F) measure (Cella D, et al., Oncology1997; 11:232-5). Psoriasis-related assessments were the target lesionassessment, the physician's global assessment for psoriasis and theDermatology Life Quality Index (DLQI) (Finlay A Y, et al., Clinical ExpDermatol 1994:19:210-6). The Target Lesion assessment evaluated targetlesions for erythema, induration and scaling, each on a scale of 0(best) to 5 (worst), with a total plaque score of 0-15.Psoriasis-related assessments were conducted only for patients with alesion that, at baseline, was cm in diameter and had a plaque score ≧6.

Post-hoc analyses of ACR response rates at Week 12 were performed fortreatment group subsets defined according to the following parameters:MTX use at baseline (yes/no), DMARD use at baseline (yes/no),non-steroidal anti-inflammatory drug use at baseline (yes/no),corticosteroid use at baseline (yes/no), baseline RF-positive ornegative, baseline C-reactive protein concentration (CRP) ≧1 mg/L or <1,and male or female.

The safety of adalimumab was assessed by measuring vital signs at everystudy visit, performing routine hematologic and clinical chemistry bloodtests and urinalyses throughout the study, and recording adverse eventsthroughout the study. Serological tests for rheumatoid factor andantinuclear antibodies were performed only at baseline visits.

Statistical Analyses

To provide ≧0.90% power to detect a difference in responses at α=0.05for a projected Week 12 ACR20 rate of 60% for the adalimumab group and25% for the placebo group, ≧50 patients per group were needed. Forefficacy and safety analyses, the intention-to-treat population wasdefined as all patients who received at least 1 dose of studymedication. After Week 12, the ITT population for the placebo arm wasdefined as those patients who received at least one dose of open-labeladalimumab. All statistical tests were 2-sided, and comparisons wereperformed with α=0.05 unless stated otherwise.

The percentages of patients who achieved an ACR20 in each group at Week12 were compared by using the Cochran-Mantel-Haenszel test, withbaseline DMARD use as the stratification factor. ACR20 response rates attime points other than Week 12 and ACR50 and ACR70 rates at all timepoints were analyzed using Fisher's Exact test and combining baselineDMARD-use categories. PsARC responses and comparisons of the numbers ofpatients in the physician's global assessment of psoriasis diseaseactivity categories “Clear” and “Minimal” with the numbers in othercategories were analyzed using the Cochran-Mantel-Haenszel test, withbaseline DMARD use as the stratification factor. The mean changes frombaseline in the HAQ DI, Target Lesion response, DLQI, FACIT-F and SF-36scores, as well as patient's assessment of pain, patient's globalassessment of disease activity, and physician's global assessment ofdisease activity, were compared (adalimumab vs. placebo) using a two-wayanalysis of variance model that included factors for baseline DMARD useand treatment. For missing data, nonresponder imputation (i.e., missingresponses were counted in the nonresponder category) was used foranalysis of ACR and PsARC responses, and last observation carriedforward was used for all other efficacy measures. Statisticalsignificance was not determined for comparisons involving results afterWeek 12.

Adverse events (AEs) were summarized by incidence and severity. TheFisher's exact test was used to compare the incidences of reported AEsin each group.

Results

102 patients were enrolled in the study, 100 of whom received study drug(51 adalimumab, 49 placebo). Two patients randomized to placebo neverreceived study drug: one because of withdrawn consent, and the otherbecause evidence from the initial evaluation indicated that the patientwas not in generally good health. Overall, 96 patients (50 adalimumab,46 placebo) completed the 12-week, double-blind, placebo-controlledportion of the study. The one patient from the adalimumab arm who didnot complete the blinded period was allowed to enter the open-labelextension. Of the 97 patients enrolled in the extension study, 92completed 12 weeks of open-label adalimumab treatment. Three patientswithdrew due to an adverse event, and two patients withdrew for otherreasons. Overall, the baseline demographics, medication usage, anddisease severity characteristics were similar between treatment groups.The mean CCRP concentration and the percentage of patients with anegative rheumatoid factor (RF) test were statistically significantlygreater in the placebo group (Table 41). At baseline, 62 patients (32adalimumab, 30 placebo) had evaluable target lesions and were thereforeeligible for psoriasis evaluations (Table 41).

Efficacy: Efficacy at Week 12 ACR Response Rates and Core ACRAssessments.

At Week 12, 39% of adalimumab patients achieved an ACR20 response,compared with 16% of placebo patients (A=23% [95% CI, 5%-41%], p=0.012).Statistically significantly more adalimumab than placebo patients alsoachieved ACR50 (25% vs. 4%, p=0.001) and ACR70 (14% vs. 1%, p=0.013)responses at Week 12 (Table 40).

TABLE 40 Week 12 Week 24 Placebo Adalimumab Placebo/adalimumabAdalimumab (n = 49) (n = 51) (n = 46) (n = 51) ACR20 16 39* 57 65 ACR502 25† 37 43 ACR70 0 14* 22 27

Reductions in the ACR components of pain, patient's and physician'sglobal assessments of disease activity, and physical function (HAQ DI)were all statistically significantly greater at Week 12 for adalimumabvs. placebo patients (Table 41). Table 41 shows that baseline diseasecharacteristics were similar between both groups except for a higher CRPvalue in the placebo arm.

TABLE 41 Baseline demographic and clinical characteristics AdalimumabPlacebo 40 mg eow (n = 49) (n = 51) Characteristic Age (years) 47.7 ±11.3 50.4 ± 11.0 Male, n (%) 25 (51.0) 29 (56.9) White, n (%) 46 (93.9)50 (98.0) Weight (kg) 88.5 (21.1) 91.5 (22.5) Rheumatoid factornegative* 48 (98.0) 41 (80.4) Duration of psoriasis (years) 13.8 ± 10.718.0 ± 13.2 Duration of psoriatic arthritis 7.2 ± 7.0 7.5 ± 7.0 (years)Moll and Wright subtype, n (%) Symmetric polyarthritis 41 (83.7) 42(82.4) Asymmetric oligoarthritis 7 (14.3) 5 (9.8) Distal interphalangeal0 3 (5.9) arthropathy Spondylitis 1 (2.0) 1 (2.0) Arthritis mutilans 0 0Dactylitis (overall severity) 2.5 ± 4.3 2.9 ± 5.1 Enthesitis (totalsites) 1.0 ± 1.3 0.9 ± 1.2 Medications Use of previous DMARDs, n (%) 49(100) 51 (100) Use of DMARDs at baseline, 33 (67.3) 33 (64.7) n (%) Meannumber of previous 2.1 ± 1.3 1.7 ± 0.9 DMARDs, n Use of previousmethotrexate, 39 (79.6) 41 (80.4) n (%) Use of methotrexate at 23 (46.9)24 (47.1) baseline, n (%) Use of previous NSAIDs, n (%) 48 (98.0) 46(90.2) Use of NSAIDs at baseline, 42 (85.7) 37 (72.6) n (%) Use ofprevious oral 15 (30.6) 10 (19.6) corticosteroids, n (%) Use of oralcorticosteroids at 9 (18.4) 4 (7.8) baseline, n (%) Core ACR AssessmentsSwollen joint count (0-76) 18.4 ± 12.1 18.2 ± 10.9 Tender joint count(0-78) 29.3 ± 18.1 25.3 ± 18.3 Patient's assessment of pain 49.1 ± 23.543.3 ± 23.4 (0-100 mm VAS) Patient's global assessment 46.3 ± 24.6 42.9± 22.4 of disease activity (0-100 mm VAS) Physician's global assessment57.1 ± 16.2 52.5 ± 17.1 of disease activity (0-100 mm VAS) HAQ DI (0-3)1.0 ± 0.7 0.9 ± 0.5 C-reactive protein (mg/dL)^(†) 1.6 ± 1.7 1.0 ± 1.0Median (range) 0.9 (0.0-7.0) 0.7 (0.0-4.5) Quality of Life AssessmentsSF-36 Physical Component 32.7 ± 11.3 34.9 ± 9.2  Summary score (0-100)FACIT-F score (0-52) 31.1 ± 12.3 34.5 ± 10.9 Target Lesion Assessments n= 30 n = 32 Target lesion, n (%) 30 (61.2) 32 (62.7) Target lesion score(0-15) 8.1 ± 2.3 7.9 ± 1.8 Dermatology Life Quality 6.2 ± 5.8 7.6 ± 6.3Index score (0-30) Physician's global assess- 0 1 (3.1) ment forpsoriasis (“Clear” or “Almost Clear”), n (%) Values are mean ± SD unlessotherwise noted. *p ≦ 0.01 based on a Fisher's Exact test. ^(†)p ≦ 0.05based on analysis of variance with baseline DMARD use and treatment asfactors. P-values not calculated for medication-related categories;elsewhere, p > 0.05 unless otherwise indicated. ACR = American Collegeof Rheumatology; DMARDs = disease-modifying antirheumatic drugs; eow =every other week; FACIT-F = 13-item fatigue scale of the FunctionalAssessment of Chronic Illness Therapy measure; HAQ DI = HealthAssessment Questionnaire Disability Index; NSAIDs = non-steroidalanti-inflammatory drugs; SF-36 = Short Form 36 Health Survey; VAS =visual analog scale.

Patients in the adalimumab group had a numerically greater meanreduction in CRP concentration at Week 12, compared with placebopatients (−0.5 vs. 0.0, p=0.051). The mean reductions in SJC and TJCwere numerically greater in the adalimumab group (−5.7 for SJC and −9.7for TJC) compared with the placebo group (−1.9 for SJC and −6.2 forTJC), but the differences were not statistically significant (Table 42).

TABLE 42 Changes from baseline in secondary efficacy measurements Week24 Week 12 Placebo/ Placebo Adalimumab Adalimumab Adalimumab Assessment(n = 49) (n = 51) P-value* (n = 46) (n = 51) Core ACR AssessmentsSwollen joint count −1.9 ± 11.5  −5.7 ± 13.7 0.140  −9.4 ± 13.9  −9.1 ±11.3 (0-76) Tender joint count −6.2 ± 10.3  −9.7 ± 17.3 0.231 −19.3 ±14.5 −15.7 ± 17.0 (0-78) Patient's assessment of  0.2 ± 23.1 −15.4 ±25.6 0.002 −24.8 ± 24.4 −19.6 ± 25.4 pain (0-100 mm VAS) Patient'sglobal −0.4 ± 24.9 −14.8 ± 24.5 0.004 −19.8 ± 25.9 −20.6 ± 24.0assessment of disease activity (0-100 mm VAS) Physician's global −9.7 ±18.2 −21.4 ± 22.4 0.005 −32.3 ± 20.9 −33.5 ± 19.5 assessment of diseaseactivity (0-100 mm VAS) HAQ DI (0-3) −0.1 ± 0.3  −0.3 ± 0.5 0.010 −0.4 ±0.4 −0.3 ± 0.5 C-reactive protein 0.0 ± 1.4 −0.5 ± 1.2 0.051 −1.3 ± 1.5−0.5 ± 0.8 (mg/dL) Additional PsA Assessment PsARC, n (%)^(†) 12 (24) 26(51)   0.007 32 (70)   38 (74)   Psoriasis Assessments Target lesionscore n = 30 n = 32 <0.001 n = 29 n = 32 (0-15) −0.3 ± 3.1  −3.7 ± 3.3−4.9 ± 3.4 −4.5 ± 3.3 Physician's global n = 30 n = 32 0.002 n = 29 n =32 assessment for psoriasis   2 (6.7) 13 (40.6) 14 (48.3) 18 (56.3)(“Clear”/“Minimal”), n (%)^(†) Dermatology Life n = 28 n = 32 0.171 n =26 n = 32 Quality Index score −1.7 ± 5.3  −3.4 ± 4.5 −3.9 ± 6.4 −3.5 ±5.1 (0-30) Quality of Life Assessments SF-36 PCS (0-100) n = 45 n = 490.082 n = 40 n = 50 2.8 ± 7.1  5.7 ± 8.5 11.7 ± 9.1  8.6 ± 7.4 SF-36 MCS(0-100) n = 45 n = 49 0.242 n = 40 n = 50 −0.6 ± 7.82  1.1 ± 7.40  0.3 ±9.7  1.9 ± 8.2 FACIT-F score (0-52) n = 46 n = 49 0.783 n = 41 n = 502.3 ± 6.7  2.6 ± 7.1  5.6 ± 9.2  2.9 ± 8.0

The ACR20 response rate was greater for adalimumab than placebo by Week2 (FIG. 5), with the difference becoming statistically significant byWeek 4 (p=0.001). Statistically significant differences were firstobserved at Week 4 for ACR50 (p≧0.05) (FIG. 6) and Week 12 for ACR70(p≧0.05) (FIG. 7). For adalimumab patients, the Week 12 ACR20/50/70response rates were similar for those who at baseline were vs. were notreceiving MTX, were vs. were not receiving a DMARD, were vs. were notreceiving an NSAID, and were vs. were not receiving oralcorticosteroids. In addition, they were similar for patients who were RFpositive vs. negative, or had a baseline serum CRP concentration ≧1 vs.<1 mg/dL. The Week 12 ACR20 for adalimumab was greater for the 29 men(52%) than for the 22 women (23%).

PsARC, Dactylitis, and Enthesitis Assessments.

The efficacy of adalimumab in treating the signs and symptoms ofPsA-associated musculoskeletal disease was assessed via severaladditional measures (Table 42). At Week 12, the PsARC response rate forthe adalimumab group (51%) was statistically significantly greater thanfor the placebo group (24%) (p=0.007). At Week 12, adalimumab led tonumerically greater mean reductions, compared with placebo, in thedactylitis score (mean change of −2.4 for adalimumab vs. −1.4 forplacebo, p>0.05) and the enthesitis score (−0.5 vs. −0.2, p>0.05).

Psoriasis Assessments.

At Week 12, the mean Target Lesion score had decreased from baseline by3.7 units for adalimumab patients vs. 0.3 units for placebo patients(p≧0.001) (Table 42). At Week 12, the physician's global assessment forpsoriasis was “Clear” or “Minimal” for significantly more adalimumabpatients (40.6%, 13/32) than placebo patients (6.7%, 2/30) (p=0.002)(Table 42).

Quality of Life Assessments.

At Week 12, significant mean improvements from baseline in the PhysicalFunctioning (p=0.027), Bodily Pain (p=0.007), General Health (p=0.017),and Mental Health (p=0.009) domains of the SF-36 were observed foradalimumab vs. placebo (data not shown). Numerically greater meanimprovements were also observed for adalimumab, compared with placebo,in the Vitality domain (p=0.070), and the Role—Physical, SocialFunctioning, and Role—Emotional domains (all p>0.10) of the SF-36. AtWeek 12, numerically greater mean improvements were observed foradalimumab vs. placebo in the SF-36 PCS (5.7 vs. 2.8, p=0.082) and, to alesser degree, the MCS (1.1 vs. −0.6, p=0.242) scores (Table 42). Duringthe first 12 weeks of therapy, the FACIT-F scores of the two treatmentgroups improved by similar degrees, each <4, the unit improvement neededto be clinically meaningful (Table 42) (Cella et al, supra). Theadalimumab group exhibited a numerically greater improvement in the DLQIfrom baseline to Week 12 vs. placebo, with mean changes from baseline of−3.4 vs. −1.7 (p=0.171) (Table 42).

Efficacy at Week 24 Arthritis Assessments During the Open-Label Period.

After 24 weeks of therapy (12 weeks double-blind plus 12 weeksopen-label), the ACR20/50/70 response rates for the 51 adalimumabpatients were 65%, 43%, and 27% (n=51), indicating that their arthritiscontinued to improve beyond Week 12. For the 46 patients who hadinitially received placebo and started adalimumab at Week 12, rapidimprovement occurred during open-label therapy, with ACR20/50/70 ratesof 57%, 37%, and 22% observed at Week 24 (Table 40 and FIG. 5). Duringopen-label treatment, scores for the components of the ACR corecriteria—SJC, TJC, patient's assessment of pain, and patient's andphysician's assessments of disease activity—continued to improve foradalimumab patients and showed a markedly increased rate of improvementfor placebo patients, with similar total improvements observed for thetwo groups at Week 24 (Table 42). PsARC responses were observed at Week24 in 70% of patients in the placebo/adalimumab group and 74% in theadalimumab arm (Table 42). The mean changes in the HAQ DI scores frombaseline to Weeks 12 and 24 were −0.1 and −0.4 for theplacebo/adalimumab group, and −0.3 and −0.3 for patients in theadalimumab arm (Table 42). By Week 24, mean CRP concentrations haddecreased from baseline by 1.3 mg/dL for patients in theplacebo/adalimumab group and 0.5 mg/dL for patients in the adalimumabarm (Table 42).

Psoriasis Assessments During the Open-Label Period.

From Weeks 12-24, the percentages of patients who achieved physician'sglobal assessments of “Clear” or “Minimal” increased by 43% (from 6.7%to 50.0%), for placebo patients treated with open-label adalimumab andby 16% (from 40.6% to 56.3%) for patients in the adalimumab arm (Table42). From Weeks 12-24, Target Lesion scores decreased by 4.4 and 0.8 forpatients from the placebo and adalimumab arms, respectively, resultingin total improvements from baseline of 4.7 and 4.5 (Table 42).

Quality of Life Assessments During the Open-Label Period.

After Week 12, the SF-36 PCS score began to improve markedly foradalimumab patients from the placebo arm, and continued to improve forpatients from the adalimumab arm, resulting in mean increases frombaseline to Week 24 of 11.7 and 8.6, respectively (Table 42). By Week24, a small mean improvement was observed in the SF-36 MCS score forpatients from each arm (Table 42). For patients from the placebo andadalimumab arms, the mean improvements in the FACIT-F scores frombaseline to Week 24 were 5.6 and 2.9, respectively, and, the meanchanges in the DLQI were −3.9 and −3.5 (Table 42).

Adverse Events Adverse Events Through Week 12.

The incidence of AEs reported during the 12 weeks of double-blindtherapy was statistically significantly lower for adalimumab (52.9%) vs.placebo (79.6%) (p=0.006) (Table 43). The incidences of AEs attributedto study drug during the first 12 weeks were 27.5% for adalimumab and28.6% for placebo. The incidences of AEs reported during the first 12weeks by % of patients in either group were similar, with the exceptionof “psoriasis aggravated” and “psoriatic arthropathy aggravated,” whichwere reported statistically significantly more frequently byplacebo-treated patients (Table 43).

TABLE 43 Adverse Events Double-Blind Open-Label Weeks 0-12 Weeks 12-24Adalimumab Adalimumab Placebo 40 mg eow 40 mg eow (n = 49) (n = 51) (n =97) Any AE 39 (79.6)* 27 (52.9) 53 (54.6) Any serious AE 2 (4.1) 1 (2.0)3 (3.1) Any AE leading to 2 (4.1) 1 (2.0) 6 (6.2) discontinuation ofstudy drug Any infectious AE 16 (32.7) 9 (17.6) 29 (29.9) Any serious 1(2.0) 0 0 infectious AE AEs reported by ≧5% of patients in eitherdouble-blind group* Upper respiratory 4 (8.2) 7 (13.7) 6 (6.2) tractinfection NOS Injection-site 6 (12.2) 6 (11.8) 0 pain Psoriasis 8(16.3)^(†) 2 (3.9) 4 (4.1) aggravated Diarrhea NOS 3 (6.1) 1 (2.0) 2(2.1) Back pain 3 (6.1) 1 (2.0) 2 (2.1) Psoriatic 7 (14.3)^(†) 1 (2.0) 1(1.0) arthropathy aggravated Headache NOS 3 (6.1) 0 3 (3.1) Valuesindicate number of patients (%). *Includes each type of AE that occurredin ≧5% of placebo group or >5% of adalimumab group during blindedtreatment. During the open-label period, two additional types of AE werereported in ≧5% of the 97 patients, cough (n = 6, 6.2%) andnasopharyigitis (n = 5, 5.2%). ^(†)p ≦ 0.05 vs. adalimumab based onFisher's exact test. AE = adverse event; eow = every other week; NOS =not otherwise specified. %

During the first 12 weeks, most AEs were mild or moderate, and therewere three serious AEs and three AEs that lead to study discontinuation(Table 43). Two serious AEs occurred in placebo patients, both of whomrequired hospitalization, one for intravenous antibiotic treatment of asublingual abscess, and the other for excision of a benign perigangliomaneoplasm. The only adalimumab patient who experienced a serious AEduring the first 12 weeks was hospitalized for treatment ofdiverticulitis and discontinued study medication. This patient wasallowed to continue in the open-label phase. Two placebo patientsdiscontinued study medication, one because of psoriatic arthropathyaggravated, and the other because of injection-site reaction. All threepatients recovered from their SAEs. The incidence of infectious AEs toWeek 12 was greater in the placebo group (32.7% vs. 17.6%). The onlyserious infectious AE occurred in a placebo patient. Changes inlaboratory values and vital signs were not clinically significant. Oneplacebo-arm patient had elevations of aspartate aminotransferase (AST)and alanine transaminase (ALT) concentrations >3 times the upper limitof normal (ULN) that resolved spontaneously prior to open-labeladalimumab. During the first 12 weeks, there were no cases oftuberculosis/granulomatous infections, demyelination, drug-inducedlupus, congestive heart failure, and malignancies, and there were nodeaths.

Adverse Events Weeks 12-24.

During the open-label period of study, the rates of AEs (54.6%), seriousAEs (3.1%), and AEs leading to discontinuation of adalimumab (6.2%) wereconsistent with those observed during the double-blind period (Table43). The 3 SAEs comprised one case of renal failure associated withrhabdomyolysis and two cases of non-cutaneous cancer (see below). Duringthe open-label period, there were no serious infectious AE,s and theoverall rate of infectious AEs (29.9%) was similar to that observed forall patients (placebo plus adalimumab) during the blinded period (25.0%)(Table 43). During the open-label period, two additional types of AEswere reported in ≧5% of all patients: cough (n=6, 6.2%) andnasopharyngitis (n=5, 5.2%). One patient from the adalimumab arm had anALT elevation >3 times ULN in the open-label extension that resolvedfollowing discontinuation of study drug. From Weeks 12-24, there were nocases of tuberculosis/granulomatous infections, demyelination,drug-induced lupus, or congestive heart failure. During this period,cancers were reported in three patients from the placebo arm, with onecase each of non-Hodgkin's lymphoma (NHL), squamous cell carcinoma ofthe skin, and adenocarcinoma of the prostate, diagnosed 3 days, 3 days,and 83 days, respectively, after administration of the first dose ofadalimumab. In retrospect, the NHL was visible on a radiograph obtainedbefore the patient had received adalimumab. No patients died from Weeks12-24.

To summarize the results, a total of 100 patients received study drug(51 adalimumab, 49 placebo). At Week 12, an ACR20 response was achievedby 39% of adalimumab patients vs. 16% of placebo patients (p=0.012), anda PsARC response was achieved by 51% with adalimumab vs. 24% withplacebo (p=0.007). At Week 12, measures of skin lesions and disabilitywere statistically significantly improved with adalimumab. After Week12, open-label adalimumab provided continued improvement for adalimumabpatients, and initiated rapid improvement for placebo patients, withACR20 response rates of 65% and 57%, respectively, observed at Week 24.Adverse events occurred in 53% of adalimumab patients during thedouble-blind period vs. 80% of placebo patients (p=0.006).

This study was a 12-week, randomized, double-blind, placebo-controlledtrial with a 12-week open-label extension that evaluated adalimumabtherapy in 100 adult patients with moderate to severe PsA who had failedDMARD therapy. The results demonstrated that adalimumab was efficaciousin reducing the signs, symptoms, and functional disability of PsA, aswell as the severity of the associated psoriasis. Adalimumab wasobserved to be generally safe and well-tolerated over 24 weeks of use.

The present study was the second Phase III trial to demonstrateadalimumab's safety and efficacy in patients with moderately to severelyactive PsA. The first such trial was Study G, which assessed treatmentin 313 patients who had failed to respond adequately to NSAID therapy(Mease et al, 2005). Both trials studied patients with long-standingdisease in a two-arm protocol comparing adalimumab 40 mg eow withplacebo. In each study, approximately half of patients receivedconcomitant MTX at baseline. Concomitant use of other DMARDs waspermitted only in the present study. In Study G, the ACR20 responserates following 12 and 24 weeks of blinded treatment with adalimumabwere 58% and 57%, respectively (Mease et al, 2005). In the presentstudy, ACR20 rates were 39% following 12 weeks of blinded adalimumab;65% for these patients following 12 more weeks of adalimumab, givenopen-label; and 57% for patients from the placebo arm following 12 weeksof open-label treatment with adalimumab. ACR50 and ACR70 rates in thepresent trial at 24 weeks, and in Study G at 12 and 24 weeks, were alsosimilar. Both studies showed statistically significant improvements inthe PsARC response with blinded adalimumab treatment. Thus, the presentstudy and Study G both demonstrate the efficacy of adalimumab intreating the arthritis component of PsA.

The present study and Study G both demonstrate that adalimumab wasefficacious in improving psoriasis and physical function. In the presentstudy, 12 weeks of adalimumab led to statistically significantimprovements in the physician's global assessment of psoriasis and inthe Target Lesion score, with each being maintained through theopen-label period to Week 24. In Study G, the Weeks 12 and 24PASI50/75/90 rates were statistically significantly greater for blindedadalimumab vs. placebo, as was the improvement in the physician's globalassessment at Week 24 (Mease et al, 2005). In the present study, themean changes in the HAQ DI observed for adalimumab-arm patients at Weeks12 and 24 (−0.3 and −0.3), and for placebo-arm patients following 12weeks of open-label adalimumab (−0.4), were similar to the −0.4 meanchange in the HAQ DI observed in Study G following 12 and 24 weeks ofblinded adalimumab treatment (Mease et al, 2005). These changes in HAQDI equal or exceed the minimum clinically important differences (MCID)reported for PsA (0.3) (Mease et al, Ann Rheum Dis 2004a; 63(Suppl1):391-2.) and RA (0.22) (Goldsmith C H, et al., Rheumatology 1993;20:561-5.).

In both the present study and Study G, there was evidence of atherapeutic effect following the first injection of adalimumab. However,during the first 12 weeks of the present study, response to adalimumabdeveloped more slowly than expected, compared with: 1) the greaterresponse rates of these patients at Week 24; 2) the greater responserates observed for placebo-arm patients at Week 24; or 3) the greaterresponse rates for Study G patients following 12 weeks of blindedadalimumab (Mease et al, 2005, supra). The reasons for the delayedresponse to adalimumab are uncertain. Most baseline parameters weresimilar for the adalimumab and placebo patients in the present study.The two parameters of disease activity with significant between-groupdifferences at baseline, the percentage of RF-negative patients and themean CRP concentration, were both lower in the adalimumab arm, butsubset analyses failed to reveal efficacy differences that could explainthe Week 12 adalimumab results. Comparisons based on whether concomitantmedications were used at baseline in the present study were alsounrevealing. A higher ACR20 response rate with adalimumab was observedfor men vs. women in the present study, but the relevance of thisobservation is unclear because the patient numbers were small and thesexes were similarly represented in each treatment arm. Moreover, in themuch larger study population of Study G, men and women had equal Week 12ACR20 response rates: 58% (Mease et al, 2005). Thus, the delayedresponse observed in the adalimumab arm of the present study was notobserved elsewhere, and was probably a result of random effects uniqueto that small treatment group.

Adalimumab was generally safe and well-tolerated during the blinded andopen-label periods of the present trial, as demonstrated by theincidence and severity of AEs, the incidence of serious AEs, thefrequency of treatment discontinuations, and the results of laboratorymonitoring. During the 12 weeks of blinded treatment, infectionsoccurred in adalimumab patients approximately half as frequently as theydid in placebo patients, but the difference was not statisticallysignificant. Upper respiratory tract infections accounted for most ofthe infections reported during blinded adalimumab treatment, consistentwith previous studies. (Keystone E C, et al., Arthritis Rheum 2004;50:1400-11; van de Putte L B A, et al. Ann Rheum Dis 2004; 63:508-16;Weinblatt M E, et al. Arthritis Rheum 2003; 48:35-45. Erratum in:Arthritis Rheum 2003; 48:855. Arthritis Rheum 2004; 22:144). There wereno cases of tuberculosis/granulomatous infections, demyelination,drug-induced systemic lupus erythematosus, or congestive heart failureduring the 24-week observation period reported here. No cancers wereobserved in adalimumab-arm patients over 24 weeks. Of the three cancersreported in placebo-arm patients during the open-label period, one wasretrospectively apparent prior to treatment with adalimumab and anotherwas diagnosed 3 days after the first adalimumab injection. The safetyprofile of adalimumab in the present study was consistent with thatreported in previous clinical studies of adalimumab in patients with PsA(Mease et al, 2005) and rheumatoid arthritis (Keystone et al, 2004; vande Putte et al, 2004; Weinblatt et al, 2003; Schiff M H, et al., AnnRheum Dis 2006; 65:889-94.), and with that of other TNF antagonists inPsA. (Mease et al, 2004; Antoni C, et al., Ann Rheum Dis 2005; 64:1150-7(b))

In summary, the present study evaluated PsA patients who had moderatelyto severely disease and inadequate response to DMARD therapy. It was thesecond Phase III trial to assess the efficacy and safety of adalimumabtherapy for long-standing PsA. Despite the relatively small size of thisstudy, adalimumab was demonstrated to have been well-tolerated, to havesignificantly reduced the signs and symptoms of arthritis, and to havesignificantly improved psoriasis and disability. In patients who hadmoderately to severely active PsA and an inadequate response to DMARDtherapy, adalimumab was well-tolerated and significantly reduced thesigns, symptoms, and disability of PsA during 12 weeks of blinded and 12weeks of open-label therapy. Adalimumab also improved psoriasis in thesepatients.

Example 12: Adalimumab Radiographic Efficacy in Patients with PsoriaticArthritis According to Demographics, Baseline Clinical Status,Methotrexate Use, and Clinical Response: Subanalysis of Study G

Study G is the largest randomized, double-blind, placebo-controlledtrial of a TNF antagonist in psoriatic arthritis (PsA) to date. Study Jdemonstrated that 24 weeks of treatment with adalimumab improvedarthritis, skin disease, and quality of life, and prevented radiographicjoint destruction in patients with PsA. Study J patients predominantlyhad long-standing, polyarticular disease, and approximately half usedmethotrexate (MTX) during the trial. It is not known whether theradiographic efficacy of adalimumab in the overall Study G populationwas restricted to any patient subsets.

This post-hoc analysis of Study G, a randomized trial of patients (pts)with psoriatic arthritis (PsA), determined whether adalimumab (ADA) hadradiographic efficacy in patient subgroups defined by selected baseline(BL) parameters or by clinical response of arthritis to therapy.

Changes from BL in the modified version of the total Sharp score (mTSS)were determined for pts grouped post-hoc by demographic parameters (age,sex, race, weight), measurements of BL clinical status (Serum C-reactiveprotein (CRP), RF, tender joint count (TJC), swollen joint count (SJC),Health Assessment Questionnarie (HAQ), methotrexate (MTX) use at BL, and20% improvement in American College of Rheumatology (ACR20) corecriteria response at Wk 24. Within each subgroup, the Wk 24 mean changein mTSS was compared for ADA vs. PBO. Analyses were restricted to ptswho had evaluable radiographs at BL and Wk 24.

The present study analyzed data from patients who had evaluableradiographs at baseline and Week 24. Numbers of joints evaluated were 78for tender joint count (TJC) and 76 for swollen joint count (SJC). SerumC-reactive protein (CRP) was assessed with a high-sensitivity assay;upper limit of normal=0.287 mg/dL. Baseline mTSS and Week 24 clinicaland radiographic outcomes were determined for patients grouped post hocby: Demographic parameters (age, sex, race, and weight); Baselineclinical characteristics (PsA disease duration, RF, TJC, SJC, HAQ DI,CRP); MTX use at baseline; and ACR response at Week 24 (included onlypatients with observed ACR scores at Week 24). Mean change in mTSS atWeek 24 was compared within each subgroup for adalimumab vs. placebo.313 patients received treatment with adalimumab or placebo in Study G.Baseline demographics and disease characteristics were similar for bothtreatment groups (see Table 1 above). Overall ACR 20/50/70 results atWeek 24 were 15/6/1 for placebo (N=162) and 57/39/23 for adalimumab(N=151) (Mease et al. Arthritis Rheum. 2005; 52:3279-3289). Radiographswere available at baseline and Week 24 for 152 placebo and 144adalimumab patients.

Of 313 pts enrolled in Study G, 296 had evaluable radiographs at BL andWk 24. By Week 24, adalimumab had significantly reduced the overallamount of radiographic progression vs. placebo. Specifically, the meanchange in mTSS from baseline to Week 24 was 1.0 for placebo (n=152), and-0.2 for ADA (n=144)(p<0.001 vs. placebo for the ADA group). For alldemographic subgroups with an adequate number of patients, the meanΔmTSS at Week 24 with adalimumab was ≦0 and was significantly lower withthan with placebo (Table 44).

TABLE 44 Mean Change in mTSS at Week 24 for Demographic Subgroups ≧40years to <60 <40 years years ≧60 years Placebo ADA Placebo ADA PlaceboADA (n = 29) (n = 36) (n = 100) (n = 84) (n = 23) (n = 24) Mean 0.6−0.3* 1.1 −0.1† 1.2 −0.1± Change in mTSS Mean 8.4 11.4 23.3 18.7 20.051.2 Baseline mTSS *p = 0.009, † p < 0.001, ± p = 0.014, vs. placeboMale Female Placebo ADA Placebo ADA (n = 84) (n = 81) (n = 68) (n = 63)Mean Change in 0.6 −0.3* 1.6 0.0† mTSS Mean Baseline 14.3 16.5 26.9 29.8mTSS *p < 0.001, † p = 0.001, both vs. placebo Caucasian Non-CaucasianPlacebo ADA Placebo ADA (n = 143) (n = 140) (n = 9) (n = 4) Mean Changein 0.9 −0.2* 2.8 0.3 mTSS Mean Baseline 19.8 22.6 23.3 11.9 mTSS *p <0.001 vs. placebo <86 kg ≧86 kg Placebo ADA Placebo ADA (n = 76) (n =76) (n = 75) (n = 68) Mean Change in 1.0 −0.1* 2.7 0.3* mTSS MeanBaseline 21.2 29.8 18.9 13.9 mTSS *p < 0.001 vs. placebo

At Week 24, the mean ΔmTSS with adalimumab was ≦0 and was significantlysmaller than placebo for patients who did or did not use MTX atbaseline, and for each subgroup defined by clinical status at baseline(Table 45). For patients with a baseline CRP ≧2.0 mg/dL, the mean mTSSat baseline was relatively high (˜44, overall); at Week 24, thedifference between the mean ΔmTSS with placebo vs. adalimumab, 3.1, wasgreater than for any other subgroup (Table 45).

TABLE 45 Mean Change in mTSS at Week 24 by Baseline MTX Use or ClinicalStatus Baseline MTX Use MTX(+) MTX(−) Placebo ADA Placebo ADA (n = 78)(n = 74) (n = 74) (n = 70) Mean Change in mTSS 1.2 −0.2* 0.9 −0.2 † MeanBaseline mTSS 25.0 21.7 14.6 22.9  *p < 0.001, † p = 0.001, both vs.placebo PsA Disease Duration <5 years ≧5 years Placebo ADA Placebo ADA(n = 57) (n = 53) (n = 95) (n = 91) Mean Change in mTSS 1.4 −0.2* 0.8−0.1* Mean Baseline mTSS 15.7 10.9 22.5 28.9 *p < 0.001 vs. placeboRheumatoid Factor (+) RF (−) RF Placebo ADA Placebo ADA (n = 14) (n =15) (n = 137) (n = 129) Mean Change in mTSS 1.0 −0.1* 1.0 −0.2† MeanBaseline mTSS 20.9 41.4 19.0 20.1 *p = 0.018, †p < 0.001 both vs.placebo Tender Joint Count TJC <20 TJC ≧20 Placebo ADA Placebo ADA (n =68) (n = 73) (n = 84) (n = 71) Mean Change in mTSS 0.6  0* 1.4 −0.3†Mean Baseline mTSS 15.7 21.1 23.4 23.6 *p = 0.006, †p < 0.001 both vs.placebo Swollen Joint Count SJC <20 SJC ≧20 Placebo ADA Placebo ADA (n =118) (n = 118) (n = 34) (n = 26) Mean Change in mTSS 0.6 −0.2* 2.5 −0.1†Mean Baseline mTSS 15.6 19.3 35.0 35.8 *p < 0.001, †p = 0.016, both vs.placebo HAQ DI Score HAQ <1.5 HAQ ≧1.5 Placebo ADA Placebo ADA (n = 107)(n = 107) (n = 45) (n = 37) Mean Change in mTSS 0.6 −0.1* 2.1 −0.4* MeanBaseline mTSS 13.6 17.8 35.1 35.3 *p < 0.001 vs. placebo C-ReactiveProtein CRP <2.0 mg/dL CRP ≧2.0 mg/dL Placebo ADA Placebo ADA (n = 110)(n = 117) (n = 42) (n = 27) Mean Change in mTSS 0.64 −0.1* 2.6 −0.5*Mean Baseline mTSS 10.7 17.5 44.3 43.0 *p < 0.001 vs. placebo. Upperlimit of normal for CRP = 0.287 mg/dL

For each CRP subgroup, the probability plot for adalimumab patients waslower than for placebo patients (FIG. 8). The smallest detectable change(SDC) of 1.88 was exceeded by 9.1% (placebo) vs. 3.4% (adalimumab) ofpatients with baseline CRP <2.0 mg/dL, and 31.0% vs. 7.4% of patientswith baseline CRP ≧2.0 mg/dL. More severe radiographic progression(e.g., ΔmTSS>4.0) occurred predominantly in placebo patients withbaseline CRP ≧2.0 mg/dL, and was nearly absent with adalimumab (FIG. 8).Mean radiographic progression with placebo treatment was greatest in theWeek 24 ACR nonresponders (ACR<20) (FIG. 8). With adalimumab treatment,the mean ΔmTSS at Week 24 was ≧0 for ACR nonresponders and ACR20responders (FIG. 8).

Overall, the mean changes in mTSS at Wk 24 were 1.0 vs. −0.2 for ptstreated with PBO vs. ADA (p<0.001). In the post-hoc analysis,statistically significantly smaller changes in the mTSS from BL to Wk 24were observed with ADA, compared with PBO, in all subgroups withsufficient pt numbers. The largest differences in progression betweenADA and PBO were observed in subgroups with BL CRP ≧2.0, SJC≧20 orHAQ≧1.5 (3.1, 2.6, and 2.5, respectively) (Table 46). The mean changesin mTSS from BL to Wk 24 were −0.2 (ADA) vs. 1.2 (PBO) (p<0.001) for ptsusing MTX at BL (51% of 296 pts, mean dosage 17.1 mg/wk), and −0.2 (ADA)vs. 0.9 (PBO) (p=0.001) for patients not using MTX at baseline. For ptswho had a <ACR20 response at Wk 24, the mean changes in mTSS at Wk 24were 0.0 (ADA, n=51) vs. 1.2 (PBO, n=121) (p=0.001), and for patientswho achieved an ACR20 response at Wk 24, they were −0.3 (ADA, n=86) vs.0.2 (PBO, n=25) (p=0.003).

TABLE 46 Mean changes in mTSS by patient subgroup PBO ADA BL Week 24 BLWeek 24 Pt mTSS ΔmTSS mTSS ΔmTSS subgroup N (Mean) (Mean ± SD) N (Mean)(Mean ± SD) p value* CRP < 2.0 110 10.7 0.4 ± 1.25 117 17.5 −0.1 ± 1.25<0.001 CRP ≧ 2.0 42 44.3 2.6 ± 5.03 27 43.0 −0.5 ± 1.87 <0.001 SJC < 20118 15.6 0.6 ± 1.74 118 19.3 −0.2 ± 1.23 <0.001 SJC ≧ 20 34 35.0 2.5 ±5.25 26 35.8 −0.1 ± 1.98 0.016 HAQ < 1.5 107 13.6 0.6 ± 1.85 107 17.8−0.1 ± 1.15 <0.001 HAQ ≧ 1.5 45 35.1 2.1 ± 4.58 37 35.3 −0.4 ± 1.92<0.001 *By analysis of variance, with treatment group, BL MTX use, andextent of psoriasis as factors, and ranked BL mTSS as covariate.

In this post hoc analysis of Study G, the Week 24 mean change in mTSSwith adalimumab was ≦0, and was significantly smaller than with placebo,for all adequately large patient subgroups, including those defined byweight, SJC, and CRP.

For pts with PsA in Study G, ADA had radiographic efficacy at Wk 24 inevery assessable subgroup. Efficacy was observed whether or not pts usedMTX at BL or had an ACR20 response at Wk 24. Pts with a BL CRP ≧2.0 hadparticularly severe radiographic progression, suggesting that CRP may bea marker for aggressive joint destruction in PsA, and that ADA inhibitsradiographic progression in such pts. Adalimumab inhibited the meanradiographic progression at Week 24 compared with placebo, whether ornot patients were ACR20 responders

Example 13: Adalimumab (HUMIRA®) is Effective and Safe in TreatingPsoriatic Arthritis (PsA) in Real-Life Clinical Practice: PreliminaryResults of Study P

Psoriatic arthritis (PsA), a seronegative spondylarthropathy, is oftenprogressive and disabling. PsA has been reported in more than 30% ofpsoriasis patients (Peters et al. Am J Health Syst Pharm 2000;57:645-62) and a great percentage of these patients have progressive,destructive arthritis leading to a significantly poorer quality of life(de Arruda L H F, de Moraes A P F. Br J Dermatol 2001; 144 (Suppl.58):33-6). Traditional treatment approaches in PsA include nonsteroidalanti-inflammatory drugs, corticosteroids and disease-modifyingantirheumatic drugs (DMARDs). Frequently used DMARDs includesulfasalazine, methotrexate, cyclosporine, and leflunomide. Clinicaltrials with adalimumab in patients with PsA have shown significantresults in improvement of joint and skin disease, quality of life, andfunction (Mease et al. Arthritis Rheum 2005; 52:3279-89)

Efficacy and safety of anti-TNFs in patients (pts) with active PsA havebeen confirmed in clinical trials and supported by post-marketing data.Study P, a prospective, open-label trial, examined the efficacy andsafety of adalimumab (ADA) in a large number of pts with active PsA, inreal-life clinical practices, including pts with various comorbidities,pts who had been treated unsuccessfully with other TNF antagonists,and/or pts who were receiving various concomitant DMARDs.

Methods included the following: unsatisfactory response or intoleranceto at least one prior DMARD was required for enrollment in STEREO. Thepatient enrollment was in accordance with the current nationalguidelines for treatment of PsA with TNF inhibitors. Patients withactive PsA received adalimumab 40 mg every other week (eow)subcutaneously (sc) in addition to their existing, but insufficient, PsAtherapy. Active PsA was defined by ≧3 tender and ≧3 swollen jointsdespite standard PsA therapy.

Key efficacy outcomes measured included: ACR20/50/70; Tender Joint Count78 (TJC 78) and Swollen Joint Count 76 (SJC 76); Change in DiseaseActivity Score 28 (DAS28); Health Assessment Questionnaire (HAQ);Physician's Global Assessment for Psoriasis (PGA); and Dermatology lifequality index (DLQI). Efficacy data and adverse events (AE) werecollected at Weeks 2, 6, and 12 during the 12-week period and at Week 20for those patients who optionally continued the study after Week 12

Thus, adult patients with active PsA, who had insufficient responses toat least 1 prior DMARD, received ADA 40 mg sc every other week (wk) for12 weeks in the Study P trial. Treatment was optionally extended to Week20 when ADA was not generally available by Week 12. Efficacy evaluationson joints and skin and routine safety evaluations were conducted atWeeks 2, 6, and 12, and optionally at Week 20. Adverse events (AE) werecollected throughout the treatment period.

As of April 2006, 253 patients (52% male), of the total 441 from 85sites in 9 European countries enrolled in Study P, had completed Week12. Mean baseline characteristics of these patients included: age, 49yrs; psoriasis duration, 20 yrs; and PsA duration, 11 yrs. Dactylitiswas present in 30% of patients, and enthesitis of achilles-tendon and/orplantar-facia in 32% of patients.

Baseline Characteristics

At baseline, patients with prior exposure to etanercept (ETN) and/orinfliximab (IFX) had a slightly higher disease activity than priorbiologic-naïve patients (Table 47). Patients with prior biologic therapywere somewhat more limited in their physical function, as measured bydisability index Health Assessment Questionnaire (HAQ) (Table 47).

TABLE 47 Prior No prior Biologics All Biologics (ETN, IPX) Patients (N =185) (N = 47) (N = 253) Age (mean, years) 49 ± 11 47 ± 12 49 ± 12 Male,% 53 45 52 Body Weight (kg) 83 ± 19 82 ± 18 83 ± 19 Duration of PsA(years) 11 ± 9  12 ± 8  11 ± 9  Duration of Psoriasis (years) 20 ± 13 20± 14 20 ± 14 Dactylitis (% of patients) 30 26 30 Enthesitis (% ofpatients) 32 34 32 TJC (0-78) 17.6 ± 12.7 16.4 ± 12.0 17.6 ± 12.5 SJC(0-76) 9.7 ± 6.4 7.0 ± 3.7 9.3 ± 6.2 DAS28 4.7 ± 1.1 4.9 ± 1.2 4.8 ± 1.2HAQ 1.2 ± 0.6 1.4 ± 0.6 1.2 ± 0.6 PGA (“Clear”/“Almost 36 39 35 Clear”),% DLQI 6.1 ± 6.2 7.4 ± 6.8 6.4 ± 6.4 Mean values ± SD except percentagesat screening (Week 0). Data records for 21 patients with prior therapieswill be completed at trial end. ETN = etanercept; IFX = infliximab.Observed values.

Key efficacy outcomes are summarized in Table 48. 20% of patients hadfailed prior etanercept and/or infliximab therapy but responded well toADA. ADA was well-tolerated, with 19 serious adverse events (SAE)reported for all 441 patients exposed to ADA. SAEs possibly related toADA, as defined by the investigator, included abdominal pain, anemia,dental abscess, urosepsis, fever with reduced general condition,allergic reaction, and severe hip pain. No new safety events onadalimumab were observed.

TABLE 48 Efficacy of Adalimumab Up to Week 12 Efficacy CriteriaScreening Week 2 Week 6 Week 12 ACR20 (%) — 38 60 72 ACR50 (%) — 14 3549 ACR70 (%) — 2 13 27 TJC (0-78) 17.6 11.6 8.7 7.3 SJC (0-76) 9.3 5.23.2 2.3 HAQ 1.20 0.96 0.91 0.86 DAS28 4.8 3.4 2.9 2.6 PGA(“Clear”/“Almost 35 39 53 65 Clear”, %) DLQI (0-30)† 6.4 NA± NA± 2.8Mean values except percentages. *PGA = physician's global assessment ofpsoriasis (7-point scale), †DLQI = Dermatology Life Quality Index(questionnaire), ±NA = not available. Completer analysis, observedvalues, n = 253.

Adalimumab treatment was effective as assessed by ACR response rates upto Week 12 in patients with moderately to severely active PsA (Table49).

TABLE 49 ACR Responses Up to Week 12 Week 2 Week 6 Week 12 ACR20 (%Patients) 38 60 72 ACR50 (% Patients) 14 35 49 ACR70 (% Patients) 2 1327

Adalimumab had a similar effect on ACR response rates in patients whowere biologic-naïve compared to those treated with prior biologictherapy at Week 12 (Table 50).

TABLE 50 ACR Responses in Biologic Naïve Patients and Patients withPrior Biologics at Week 12 Biologic Naïve (n = 185) Prior Biologics (n =47) ACR20 71 69 ACR50 51 42 ACR70 28 20

Observed Values

Adalimumab was effective in decreasing the number of tender and swollenjoint counts up to Week 12 (Table 51).

TABLE 51 Mean Change from Baseline in Tender and Swollen Joint Countsthrough Week 12 TJC SJC Week 0 17.6 9.3 Week 2 11.6 5.2 Week 6 8.7 3.2Week 12 7.3 2.3

Total patient population includes with and without prior biologictreatment (n=253). Observed values.

Disease activity scores in the total patient population with exposure toadalimumab continued to decrease compared to baseline through Week 12,as measured by the mean change from baseline in DAS28 (Table 52).

TABLE 52 Mean Change from Baseline in DAS28 Scores through Week 12 MeanChange from Baseline Week 2 −1.4 Week 6 −1.9 Week 12 −2.2

Total patient population includes with and without prior biologictreatment (n=253). Observed values.

Disease activity scores in prior-biologic patients with exposure toadalimumab continued to decrease compared to baseline through Week 12,as measured by the mean change from baseline in DAS28 (Table 53).

TABLE 53 Mean Change from Baseline in DAS28 Scores through Week 12 byPrior Exposure too Biologic Anti-TNFs Biologic Naïve (n = 185) PriorBiologics (n = 47) Week 2 −1.4 −1.2 Week 6 −1.9 −1.6 Week 12 −2.2 −2.1

Observed Values

Health assessment in the total patient population with exposure toadalimumab continued to decrease compared to baseline through Week 12,as measured by the mean change from baseline in HAQ (Table 54).

TABLE 54 Mean Change from Baseline in HAQ Scores through Week 12 MeanChange from Baseline Week 2 −0.24 Week 6 −0.29 Week 12 −0.34

Total patient population includes with and without prior biologictreatment; N=153. MCID was −0.3 (Mease P J, et al., Ann Rheum Dis. 2004;63 (Suppl 1): 391-392. Observed values.

Disease activity scores in prior-biologic patients with exposure toadalimumab continued to decrease compared to baseline through Week 12,as measured by the mean change from baseline in DAS28 (Table 55).

TABLE 55 Mean Change from Baseline in HAQ Scores through Week 12 byPrior Exposure to Biologic Anti-TNFs Biologic Naïve (n = 185) PriorBiologics (n = 47) Week 2 −0.24 −0.30 Week 6 −0.29 −0.28 Week 12 −0.34−0.36

Observed Values. MCID was −0.3 (Mease P J, et al., Ann Rheum Dis. 2004;63 (Suppl 1): 391-392.

At Week 12, the percentage of adalimumab-treated patients with a PGAscore of “Clear”/“Almost Clear” was greater in both biologic-naïve andprior-biologic patient groups than at screening (Table 56).

TABLE 56 PGA “Clear”/“Almost Clear” At Screening and Week 12 BiologicNaïve (n = 185) Prior Biologics (n = 47) Screening 36 39 Week 12 66 63

Observed Values.

At Week 12, patients treated with adalimumab achieved an improvement inquality of life, as measured by mean DLQI scores (Table 57).

TABLE 57 Mean DLQI Scores at Week 12 Mean DLQI Scores (n = 253)Screening 6.4 Week 12 2.8

Observed Values. Total patient population includes with and withoutprior biologic treatment.

The overall results showed that adalimumab was overall well-toleratedduring the 12-week exposure. Out of 441 patients exposed to adalimumab,19 (4%) serious adverse events (SAE) were reported. SAEs possiblyrelated to adalimumab, as defined by the investigator, includedabdominal pain, anemia, dental abscess, urosepsis, fever with reducedgeneral condition, allergic reaction, severe hip pain, and hypersomnia.The spectrum of adverse events was similar to those reported in pivotalstudies with adalimumab and in studies with other biologics. Rates ofwithdrawal because of adverse events were similar among patients naïveto biologics and those exposed to prior biologics. No new safetyconcerns following adalimumab therapy were observed. The percentage ofpatients who prematurely dropped out before reaching Week 12 for variousreasons was low (8%)

In conclusion, ADA provided clinically significant joint and skinimprovements. Study P data confirm results observed in earlier ADApivotal trials. The benefit-risk ratio of ADA-treated pts with PsA inreal-life clinical practice is positive. In patients with long-standingPsA and an insufficient response to prior biologic therapies inreal-life clinical practice, the addition of adalimumab let toclinically important skin and joint improvements at Week 12 in all keyefficacy parameters. Adalimumab was well-tolerated in patients who weretreated with or without prior biologics, particularly ETN and IFX.Withdrawal rates because of lack of efficacy or intolerance within 12weeks were low.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims. The contents of allreferences, patents and published patent applications cited throughoutthis application are incorporated herein by reference.

What is claimed:
 1. A method of treating PsA in a subject having asubtherapeutic response to treatment with a TNFα inhibitor comprisingadministering the TNFα inhibitor to the subject on a weekly dosingregimen, such that PsA is treated.